Stage IV Melanoma

Overview

Patients with stage IV, or metastatic, melanoma have cancer that has spread from its site of origin to distant lymph nodes and/or distant sites. Additional prognostic factors for stage IV melanoma include site of distant metastases and elevated blood enzyme LDH levels. Distant lymph node metastases and lung metastases have a better prognosis than other distant metastases, such as the brain or liver.

A variety of factors ultimately influence a patient’s decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient’s chance of cure, or prolong a patient’s survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment.

The following is a general overview of the treatment of stage IV melanoma. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician.

Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials.

Patients with stage IV melanoma cannot be cured with surgery alone and appear to benefit modestly with currently approved systemic therapies. There are many choices of therapy for patients with stage IV melanoma; however, the majority of patients still experience cancer progression. Clinical responses are observed in 5-10% of patients with stage IV melanoma, irrespective of the mode of treatment. These responses and the fact that some are long lasting, have generated optimism about the treatment of stage IV melanoma.

Treatment strategies that are part of both curative and palliative approaches include single agent and combination chemotherapy; biological therapy with interferons; interleukins; vaccines; combination therapy; external beam radiation; isolated limb perfusion techniques and surgery. Chemotherapy combined with biologic agents offers the promise of higher response rates and long-term durable remissions and is the focus of most current studies of initial treatment of metastatic melanoma.

Treatment with Chemotherapy

DTIC (dacarbazine) is the standard chemotherapy agent for the treatment of metastatic melanoma, with an overall response rate of approximately 15-20%. No trial directly comparing DTIC to different chemotherapy combinations has demonstrated superiority of drug combinations over DTIC alone. Nevertheless, several three-drug regimens (DTIC, Platinol® and carmustine) have demonstrated response rates between 30% and 50%. The duration of response to these regimens averages 6-9 months, with average survivals of 6 to 11 months. The fraction of patients surviving one and two years following treatment may be a better measure of effectiveness than average duration of survival. Using this measurement, combination chemotherapy may be superior to any single agent.

A new chemotherapy drug, Temodal®, may be as effective or more effective than the standard chemotherapy agent, dacarbazine, in improving survival time and quality of life for patients with metastatic melanoma. In a large clinical trial, 305 patients with metastatic melanoma were assigned to receive treatment with either oral Temodal® or intravenous dacarbazine. The results of this preliminary study show that the response rate of patients receiving Temodal® was 13.5%, compared to 12.1% for those receiving dacarbazine, with a complete response rate of 3% in both treatment groups. The average survival time was 7.7 months for patients taking Temodal®, and 6.4 months for those receiving dacarbazine. In terms of health-related quality of life, patients receiving Temodal® showed better maintenance of or improvement in physical function and less fatigue and insomnia after 12 weeks than did those receiving dacarbazine. Oral Temodal® was at least as effective as intravenous dacarbazine and may provide an oral alternative for the treatment of advanced melanoma.

Treatment with Biologic Agents

Biological agents, also called immunotherapy, are treatments that stimulate or restore the ability of the immune system to fight the cancer. There are several substances that boost, direct or restore normal immune defenses and include interferons, interleukins, vaccines and monoclonal antibodies.

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.

Long-term results from a clinical trial evaluating high-dose Proleukin® in 270 patients with metastatic melanoma have recently been reported. In this trial, 16% of patients achieved a partial or complete disappearance of their cancer following high-dose Proleukin®. The average duration of all responses was approximately 9 months. For patients who achieved a complete disappearance of cancer following treatment, the average duration of response has not yet been established. Approximately seven years following therapy, the overall survival rate was approximately 11%. These long-term anti-cancer responses and survival indicate that high-dose Proleukin® remains an extremely effective treatment option for a subset of patients with metastatic melanoma.

Several other clinical trials have been conducted to evaluate treatment combinations consisting of Proleukin® and/or interferon with or without combination chemotherapy in patients with metastatic melanoma. Although it appears that combinations of Proleukin®, interferon and combination chemotherapy (typically dacarbazine and Platinol® with or without Velban®) produce superior response rates, it is still unclear whether this combination can improve overall survival. Clinical trials are ongoing to directly compare different treatment strategies in patients with metastatic melanoma in order to determine optimal treatment regimens.

Alpha Interferon: Alpha interferon has shown anti-cancer activity in metastatic melanoma as a single agent and in combination with chemotherapy agents and Proleukin®. As a single agent, alpha interferon is associated with a response rate of 15%, which is comparable to Proleukin® or single agent chemotherapy with DTIC. For the treatment of metastatic melanoma, alpha interferon is most often combined with chemotherapy and/or Proleukin® and is rarely used as a single agent. The role of alpha interferon was evaluated in a review of 1,600 patients with metastatic melanoma. The overall response rate for patients receiving regimens that contained alpha interferon was 24%, compared to 17% for patients treated with regimens that did not contain alpha interferon. There was also an improved survival for patients receiving alpha interferon compared to those receiving regimens that did not contain alpha interferon. The combination of alpha interferon and Proleukin® appears to have greater anti-cancer activity than either agent alone.

Combination Treatment with Biologic Agents and Chemotherapy

The administration of chemotherapy combined with immunotherapy appears to be the most promising currently available therapy for metastatic melanoma. Response rates of more than 50% have been reported in several single institution clinical studies. The greatest success of chemo-immunotherapy is its ability to produce durable complete remissions in approximately 10% of treated patients. In one clinical study, 32 patients were treated with monthly cycles of carmustine/DTIC/Platinol® chemotherapy and Nolvadex® plus Proleukin® and alpha interferon. The overall response rate was 43% (13% complete and 30% partial). This regimen was well tolerated as an outpatient treatment.

Role of Hormonal Therapy

The hormonal agent Nolvadex® is an antiestrogen and produces apoptosis (cell death) in some cancers. As a single agent, it has no role in the treatment of metastatic melanoma. Phase II clinical studies, however, have suggested that Nolvadex® may add to the effectiveness of chemotherapy for treatment of metastatic melanoma in combination with chemotherapy. Some, but not all, randomized clinical trials have supported the use of Nolvadex®. Since Nolvadex® is not very toxic, it is often administered because it may be beneficial and is associated with minimal side effects.

In one clinical study, researchers in Miami sought to prolong the response and survival rates in individuals with metastatic melanoma by combining Nolvadex® with Navelbine® chemotherapy. Thirty patients with advanced melanoma that had spread to tissue surrounding the original cancer or had spread to distant parts of the body received intravenous Navelbine® plus Nolvadex®. Six patients had a partial response to this combination treatment, producing an overall response rate of 20%. Three patients had a prolonged response that lasted more than one year.

In another clinical trial, patients who had previously failed chemotherapy treatment were treated with paclitaxel chemotherapy plus Nolvadex®. The findings showed that 5 of the 21 patients responded to treatment (24%), with one having a complete response. The treatment was well tolerated by the patients. Navelbine®, paclitaxel or other chemotherapy drugs may be effective in combination with Nolvadex®.

Role of Surgery in Stage IV Melanoma

Available data suggests that patients who have a limited number of pulmonary metastases may benefit from complete removal of the metastases if they have favorable prognostic features, such as a long period of time between diagnosis and recurrence. Surgery in some patients can eradicate disease that has incompletely responded to chemotherapy and/or biological therapy and some of these patients will remain disease-free for over 5 years. Surgery can also relieve symptoms of obstruction and bleeding. Selected patients with metastatic melanoma to the gastrointestinal tract can experience prolonged survival following surgical removal of the cancer.

Role of Radiation Therapy in Stage IV Melanoma

Radiation therapy can relieve symptoms, especially pain from cancer that has spread to the bone. Radiation therapy should be considered in patients who have had surgical removal of a single brain metastasis from melanoma.

Treatment of Brain Metastasis

Brain metastasis accounts for 10-50% of reported deaths from melanoma. Radiation therapy should be considered in patients who have had surgery for removal of a single brain metastasis. There is a suggestion that radiation therapy in this situation improves survival and reduces cancer recurrences. The decision to recommend surgery should be based primarily on whether the entire melanoma can be removed and the status and number of other organs involved with metastatic cancer.

Questions to Ask Your Physician

The main issue facing patients with stage IV melanoma is choosing which initial treatment to receive. There are many clinical trials being carried out for patients with stage IV melanoma. Since no treatment is standard and effective, it may be best to consider all of the options available.

Strategies to Improve Treatment

The progress that has been made in the treatment of melanoma has resulted from improved development of treatments in patients with more advanced stages of cancer and participation in clinical trials. Future progress in the treatment of melanoma will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of melanoma.

New Treatment Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies for use as treatment is an active area of clinical research carried out in phase II clinical trials. Combining chemotherapy with biologic agents is the focus of intensive investigation, with many clinical trials ongoing. Most clinical trials include DTIC , a platinum compound (Platinol® or Paraplatin®) and a nitrosourea (carmustine) and both Proleukin® and alpha interferon. Newer drug combinations and other biologic agents will continue to be evaluated.

Allogeneic Stem Cell Transplant: Another way to utilize the immune system to treat cancer is by transplanting a new immune system into a patient. This is referred to as an allogeneic stem cell transplant, and immune cells (the graft) are transplanted from healthy individual into the patient. Prior to receiving the transplant, the patient receives high doses of chemotherapy or radiation, which “prepare” the patient to receive the donor graft. This therapy is known to cure patients with leukemia, lymphoma and other cancers. Recently, doctors at the National Heart, Lung and Blood Institute have reported the successful treatment of a patient with metastatic renal cell carcinoma using a relatively non-toxic low-dose treatment regimen to facilitate engraftment. Since melanoma has similar immunogeneic properties to renal cell carcinoma, researchers believe that allogeneic stem cell transplantation may also be an effective treatment for melanoma. Early phase clinical trials are being conducted to further define the role of allogeneic stem cell transplantation in the treatment of melanoma. To learn more, go to Allogeneic Stem Cell Transplant.

Vaccines: No vaccine has been approved by the U.S. Food and Drug administration for the treatment of metastatic disease or for the prevention of a relapse. Melanoma vaccines produce responses, often dramatic, in some patients, but effects are far from consistent. Adjuvant therapy (treatment following therapy to prevent recurrences), vaccines have shown potential benefit in phase II trials but this benefit has been limited to the minority of patients who generate a measurable immune response following vaccination. There have been some reports of dramatic responses of metastatic melanoma to a variety of vaccines. However, no standard vaccine for stage IV melanoma is available.

Biologic Therapy: One type of biologic therapy that has produced favorable preliminary results is granulocyte macrophage colony-stimulating factor (GM-CSF), a type of cytokine (a substance in the body that helps to enhance the immune system). GM-CSF is a promising option for cancer therapy because of its potential to be effective against disease without the serious side effects of many chemotherapy drugs. Cytokines, such as GM-CSF, are most effective when there is only a minimal amount of cancer remaining after surgery.

In a recent multi-center clinical trial, 48 patients with stage III and IV melanoma. underwent surgery, which resulted in the removal of all visible cancer. The patients then received GM-CSF every 28 days for 1 year. The outcomes of these patients were compared with those of past patients who had received surgery alone as treatment. The findings showed that the number of cancer recurrences were fewer in those who received GM-CSF after surgery. Moreover, the average survival time for patients treated with surgery and GM-CSF was almost 38 months, compared to 12 months for those treated with surgery alone. No significant side effects were associated with the GM-CSF therapy. The results of this study are promising and research is ongoing to determine the role of GM-CSF in the treatment of melanoma.

Maintenance Biotherapy: Results from a clinical trial conducted at the John Wayne Cancer Institute indicate that maintenance therapy consisting of Proleukin® and GM-CSF appears to significantly improve survival for patients with advanced melanoma who respond to initial biochemotherapy. The trial involved a two-phase treatment strategy, which included initial therapy and maintenance therapy. The initial phase of the trial included a regimen of chemotherapy plus biologic therapy, which stimulated the patient’s immune system to attack cancer. Patients initially received Proleukin®, interferon and GM-CSF, all substances produced by the body that stimulate different cells in the immune system through various biochemical cascades. In addition, the chemotherapy agents dacarbazine, Velban® and Platinol® were part of the initial treatment regimen. Of the 45 patients receiving initial treatment in this clinical trial, all had melanoma that had spread from the site of origin, with 62% having spread to 3 or more organs. The overall anti-cancer response rate following this initial treatment regimen was 57%, with 23% achieving a complete disappearance of their cancer.

Interestingly, in addition to the patients who achieved a complete disappearance of their cancer, 55% of patients who received the initial treatment demonstrated a halt in their cancer growth. Upon these findings, the researchers decided to continue maintenance biological therapy specifically to the subgroup of patients whose cancer had stopped growing following the initial treatment. The maintenance regimen consisted of Proleukin® and GM-CSF given in tapering “pulses” over the course of one year. One year following initial therapy, 30% of patients who received maintenance therapy were alive with no progression of cancer, compared with the historical 6% of patients treated at the same facility without maintenance therapy. The overall survival one year following the initial therapy was 69% for patients receiving the maintenance therapy, compared with the historical 31% of patients treated without maintenance therapy. No patients had to discontinue treatment due to side effects.

Phase I Trials: New anti-cancer drugs continue to be developed and evaluated in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients with advanced melanoma.

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 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.

Supportive Care: Supportive care refers to treatments designed to prevent and control the side effects of cancer and its treatment. Side effects not only cause patients discomfort, but also may prevent the optimal 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 side effects resulting from cancer and its treatment are appropriately managed. For more information, go to Supportive Care.