Patients with recurrent or refractory metastatic melanoma may be divided into 2 groups: patients who have failed initial systemic therapy (chemotherapy and/or biologic therapy) and experience progression or recurrence after an initial response to treatment or patients who have local recurrences(skin and/or regional lymph nodes) after initial surgery or surgery and adjuvant therapy.
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 recurrent or refractory 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 metastatic melanoma who have failed initial systemic therapy are infrequently cured with additional therapy. There are many choices of therapy and access to newer treatment strategies in clinical trials. These therapeutic choices may prolong survival, reduce symptoms of progressive cancer and/or offer the chance of cure. Patients need to assess their treatment options and consider their individual goals for receiving additional treatment.
Treatments that are part of curative and palliative strategies include: single agent and combination chemotherapy; biological therapy with interferons; interleukins and vaccines; combination chemotherapy and biologic 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 clinical trials. Many current clinical trials are attempting to develop the optimal schedule of combining chemotherapy and biological therapy. The role of vaccine therapy for initial management of patients with recurrent or refractory melanoma is currently not well defined, but there have been some promising results reported.
Treatment with Chemotherapy
Chemotherapy is indicated for patients whose cancer has progressed following initial treatment with biological agents such as Proleukin® and/or alpha interferon. 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.
Nolvadex® and Chemotherapy
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.
Role of Surgery
The available data suggests that surgery plays a role in the management of some patients with metastatic melanoma. Patients who have a limited number of lung metastases may benefit from surgical removal if they have favorable other 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 survive cancer-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 melanoma.
A frequently asked question is whether a second surgery can also provide benefit to patients who have a recurrence, or return of the cancer, after already having one surgery for metastatic melanoma. Researchers reviewed the treatment outcomes for 211 patients with stage IV metastatic melanoma who were deemed clinically free of cancer after surgery. The melanoma recurred in 131 of these patients after an average of 8 months, but ranging up to 7.5 years following initial treatment. After a second surgical removal of cancer from 1 to 3 sites to which the cancer had spread in the body, the average survival time after surgery was 18 months. At 5 years after surgery, 20% of patients in whom removal of all detectable cancer was complete were alive. The longer the interval between the initial treatment and the recurrence, the longer the survival time was after the repeat surgery.
These findings show that a second surgery may benefit patients who have a recurrence of metastatic melanoma, provided that the surgical removal of all detectable cancer was complete. This is an important treatment option for patients with metastatic melanoma for whom other treatments are ineffective or for those who have a partial response to biologic therapies (or immunotherapies) or chemotherapy.
Role of Radiation Therapy
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 melanoma.
Treatment of Brain Metastasis
Melanoma that has spread to the brain accounts for 10-50% of reported deaths from melanoma. A single brain metastasis can be removed surgically and radiation therapy should be considered in patients who have had surgical removal of a single brain metastasis. There is the suggestion that radiation therapy in this situation improves survival and reduces 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 lesions.
Locally Recurrent Melanoma
Following initial treatment with surgery with or without adjuvant therapy, patients are said to have locally recurrent melanoma if the cancer returns in or near its original location and cannot be found elsewhere in the body. A physical exam, CT scan, MRI, bone and PET scan should be used to rule out distant metastasis. The major determinant of therapy and treatment outcome is whether the recurrent melanoma involves the local/regional lymph nodes.
Local Recurrence Without Nodal Involvement
Following initial surgical removal of melanoma, approximately 12% of patients will experience cancer recurrence in the skin or skin graft without evidence of more widespread disease. The treatment of locally recurrent melanoma without lymph node involvement consists mainly of additional surgical removal of the cancer. To establish that the lymph nodes are not involved, patients may request a sentinel node biopsy before wide local excision. The American Joint Committee on Cancer and World Health Organization recommend sentinel node biopsy for melanoma tumors greater than 1mm.
Local Recurrence With Nodal Involvement
Surgery: If recurrence involves a cutaneous melanoma tumor and nodal involvement is expected but not established a sentinel node biopsy at the time of wide local excision may be required. A regional lymph node dissection may be performed on the neck, armpit or groin depending on the site of cutaneous recurrence or presence of palpable nodes. Associated lymph node dissection side effects may include sensory numbness, diminished mobility and intermittent swelling called lymphedema. Prognosis depends on extent of nodal involvement. In one series of 26 patients who had recurrent cutaneous melanoma of the head and neck, 38% were alive and free of disease following complete dissection of neck lymph nodes. Researchers at MD Anderson report that the 5 year cancer free survival for patients with one positive node, 2 to 4 positive nodes and more than 4 positive nodes is 48%, 36% and 21%, respectively.
Chemotherapy before Surgery for Nodal Involvement: In one study, patients received systemic chemotherapy prior to surgery. There was a 44% clinical response rate prior to surgery, but the impact of this approach on survival is unknown.
Isolated Limb Perfusion: For the past 40 years, patients have been treated with isolated limb perfusion in attempts to prevent amputation or mutilating surgery in patients with recurrences localized to a single arm or leg. This localized treatment strategy is believed to augment anti-cancer effects of chemotherapy compared with systemic (full body) delivery through the following mechanisms: 1) the chemotherapy agent does not become diluted prior to reaching the cancer by mixing with the rest of the blood from the body, 2) the chemotherapy agent is not broken down in the body through biochemical processes prior to reaching the cancer, 3) larger amounts of the chemotherapy agent can reach the cancer with fewer associated systemic side effects.
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.
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 recurrent melanoma is available.
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.
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.
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