Treatments for Stage III and Stage IV Melanoma

When melanoma cells spread to the lymph nodes (stage III) or more distant parts of the body (stage IV), including organs, the disease is considered advanced, and additional therapy usually follows surgical removal of the original (primary) skin tumor. (This may also be the case with stage II patients whose melanomas are considered at high risk of spreading to the lymph nodes or beyond.) Today, patients with metastatic melanoma can benefit from an array of treatments approved by the FDA in recent years that can extend their lives by months or years, with a rising number of patients going into long-term remission. With several effective treatments available, the decisions patients and their physicians make about which treatments to use are more important than ever, a vital part of the treatment process. A variety of factors may influence this decision.

Below, you’ll find the key treatments now available for advanced melanoma patients. Ask your physician to explain the possibilities and the reasons for selecting one treatment over another. For more extended definitions of individual treatments, please refer to our Skin Cancer Treatment Glossary.

Select a treatment to learn more about it.

  • Immunotherapy

    Some of the most important recent advances in melanoma treatment are increasingly effective new forms of immunotherapy. Using synthetic, mass-produced versions of natural immune system proteins, or by inhibiting receptors that block the immune system, immunotherapies boost the body’s ability to fight disease. New agents are adding years to many patients’ lives.

    Checkpoint Blockade Therapy
    The most successful form of melanoma immunotherapy to date is checkpoint blockade therapy, which now boasts four treatments approved by the FDA for stage IV, metastatic melanoma patients since 2011 — three individual drugs and a combined drug. Two of the individual drugs have also been approved for stage III patients who have metastases to their local lymph nodes. These treatments are significantly extending lives for many advanced (stages III and IV) melanoma patients. The medicines, all infused intravenously, have produced a bona fide revolution in melanoma treatment the past several years, giving real hope to patients.

    Checkpoint Blockade for Stage IV
    The first successful checkpoint blockade therapy was ipilimumab (Yervoy®), approved in 2011 for patients with stage IV melanoma. Ipilimumab blocks CTLA-4 (cytotoxic T lymphocyte-associated protein 4), a protein receptor that functions as an immune checkpoint or “brake” to regulate the immune system. It can inhibit activation of T cells, thereby preventing them from destroying the tumor. By blocking CTLA-4, ipilimumab allows more T cells to be produced when needed to fight a cancer. It is often referred to as anti-CTLA-4 therapy.

    A monoclonal antibody (a purified class of antibodies cloned and mass-produced in the lab from one specific type of cell or cell line), ipilimumab has yielded dramatic, sustained responses akin to “cures” in certain patients, with some surviving more than five or even 10 years. In a study of 1,861 patients treated with ipilimumab, about 22 percent lived three years or longer, and 84 percent of those survivors were estimated to be alive after five years and 10 years. One report, in fact, suggested that 20 percent of patients who received ipilimumab are alive after eight years. In contrast, only about 4 to 6 percent of patients on an earlier form of immunotherapy, interleukin-2, achieved long-term survival, and chemotherapy has never demonstrated a survival advantage.

    In 2014, the FDA approved two additional immune checkpoint-blockading drugs, pembrolizumab (Keytruda®) and nivolumab (Opdivo®). Both drugs inhibit another protein receptor (programmed death-1, or PD-1) that suppresses T cells. PD-1 can directly interact with tumor cells by binding to a molecule called programmed death ligand-1 (PD-L1), and cancer cells may use PD-L1 to hide from attack by T cells. But the anti-PD-1 drugs can release the T cells to fight the cancer.

    Both pembrolizumab and nivolumab were approved for use in patients whose melanoma has metastasized or cannot be removed by surgery. As of 2016, based on results showing they are more effective than ipilimumab or other therapies, both pembrolizumab and nivolumab can be used as frontline treatments — before other drug treatments have been tried — or as second-line treatments after other treatments have failed or stopped working. Studies have also shown that both nivolumab and pembrolizumab are safer than ipilimumab, with fewer serious side effects, produce greater response rates and are significantly more effective in fighting off melanoma. Both lead to longer periods without the disease advancing and longer survival. These agents have thus largely replaced ipilimumab as preferred options for frontline treatment, with ipilimumab still being used as a second-line therapy, as well as in conjunction with PD-1 inhibitors or other treatments.

    A 2016 study of 655 patients on pembrolizumab offered some of the most impressive results ever with advanced melanoma patients. Average survival was 23 months, and more than 40 percent of patients — whether they had been previously treated with other drugs or not — were alive three years after starting treatment, with 85 patients remaining cancer-free. The fact that the therapy worked as well for previously treated patients as for previously untreated patients is especially good news for those whose initial drug therapies have failed to work or stopped working.

    Nivolumab has produced comparable results. A 2016 report on the longest ongoing study of the drug showed 17-month average survival, with 42 percent of patients surviving three years and 34 percent surviving five.

    Other PD-1 inhibitors for advanced melanoma are being tested, along with the related experimental inhibitors MPDL3280A (atezolizumab) and BMS-936559, which block PD-L1, the ligand that binds PD-1 to T cells and deactivates them. By blocking PD-L1, these inhibitory drugs keep it from interacting with PD-1, and thus release the T cells to fight the melanoma. Recent research has also revealed that a second ligand binding to PD-1, PD-L2, may also play a part in melanoma and other cancers by restricting T cells, and future research may target it for inhibition along with PD-1 and PD-L1.

    Checkpoint Blockade for Stage III
    In late 2015, the FDA approved use of ipilimumab at an earlier stage, for stage III patients after their primary tumor is removed and lymph node disease is verified by clinical exam or sentinel node biopsy. This was the first time a checkpoint blockade therapy was used as an adjuvant therapy — a supplementary treatment that enhances the effectiveness of a primary treatment such as surgery. The goal was to prevent or slow recurrence and ideally prevent metastasis beyond the lymph nodes. Ipilimumab was also the first therapy to improve significantly upon what was once the sole existing adjuvant immunotherapy for melanoma, high-dose interferon alfa-2b (IFN-alfa-2b).

    The FDA based its acceptance of adjuvant ipilimumab on results from a phase 3 trial showing a 25 percent improvement in delaying recurrence in stage III patients treated with ipilimumab vs. placebo (27.6 months on average before the disease came back in the ipilimumab patients, vs. 17.1 months in the placebo patients). This is somewhat longer than achieved with IFN-alpha-2b.

    Longer-term follow-up of the study has produced even more important results. In 2016, researchers for the European Organization for Research and Treatment of Cancer (EORTC) published findings in the New England Journal of Medicine demonstrating that ipilimumab increased survival in these patients, reducing risk of death by 28 percent compared to placebo treatment. Five-year survival (overall survival, or OS) rates were 65.4 percent for patients in the ipilimumab group vs. 54.4 percent for those in the placebo group. All patients had previously gone through surgery to remove their primary tumors. This made ipilimumab the first proven life-extending treatment for stage III melanoma patients in history.

    In 2017, the FDA then approved the use of nivolumab as an adjuvant therapy, for stage III patients with lymph node metastases whose primary tumors have been completely removed, as well as stage IV patients with distant metastatic disease.

    The research leading to this approval showed greater than 66 percent recurrence-free survival (RFS) at 18 months with nivolumab, compared with 52 percent RFS with ipilimumab. It also showed a 35 percent reduction in the risk of recurrence or death with nivolumab compared with ipilimumab. Furthermore, serious side effects were significantly lower with nivolumab than with ipilimumab (about 14 percent of cases versus 46 percent). As a result, nivolumab generally became the frontline adjuvant therapy for melanoma over ipilimumab.

    Combined Checkpoint Blockade Therapies
    Building on the success of the individual checkpoint blockade therapies, investigators have pursued different avenues in combining them to even greater effect. In 2015, the FDA approved one such combination therapy, nivolumab-ipilimumab, for patients with metastatic or inoperable melanoma, and findings to date show it is indeed more effective than either ipilimumab or nivolumab alone. The phase 3 CheckMate-067 trial has found that the combination reduces disease progression by about 58 percent in previously untreated patients, compared with 45 percent reduction with nivolumab alone and 19 percent with ipilimumab alone. About 17 percent of patients on the combination therapy appear to have gone into complete remission. Of the initial 53 patients treated with the combination therapy, an unparalleled 68 percent have survived three years or longer.

    Combo Nivolumab-Ipilimumab for Brain Metastases

    In August, 2018, a multicenter team from 28 different medical centers in the U.S. published landmark findings using combination nivolumab-ipilimumab to treat melanoma patients who had one or more untreated brain metastases and no neurologic symptoms. Among 94 patients followed up over 14 months, 26 percent had a complete response, their brain tumors going into remission; another 30 percent had partial responses, their tumors shrinking, and an additional two percent had stable disease for at least six months. In 56 percent of the patients, the treatment also worked against melanoma tumors in other parts of the body. Until now, only about 20 percent of melanoma patients with brain metastases have survived one year on traditional treatments, but in this study, almost 82 percent of the patients were alive after a year. The study’s lead author, Hussein A. Tawbi, MD, associate professor of melanoma medical oncology at MD Anderson Center in Houston, said that the results of this study, published in The New England Journal of Medicine, should change the standard of care for such patients, who should now be offered the drug combination as part of their initial treatment.

    One thing to be aware of is that patients on the combination therapy have a higher percentage of side effects and complications, including immune-related adverse events (irAEs) such as thyroid or kidney damage, which can be serious enough to discontinue the therapy. However, some investigators suggest that for patients who have such serious reactions — even if they must be hospitalized and go on steroids for weeks or months to recover from the side effects — the ultimate life-extending benefits may be worth the risk of using the combination therapy rather than the single-agent therapies. Much of this depends on the age, health and hardiness of the patient. Until longer follow-up and survival data emerge, choosing between a solo therapy or the combination therapy will remain an important decision for doctors and patients. Meanwhile, physicians are becoming much more adept at detecting and managing irAEs earlier, when they are less damaging, and some patients can either continue on their checkpoint blockade therapy or come back to it later after symptoms have been successfully treated. 

    Oncolytic Virus Injections
    In late 2015, the FDA approved the first drug in an entirely new class of immunotherapies for melanoma: injectable oncolytic virus therapy. The drug, talimogene laherparepvec (Imlygic®), often shortened to T-VEC, is approved for local treatment of inoperable metastatic lesions in the skin or lymph nodes that recur after initial surgery.

    An oncolytic virus is one designed to specifically target, infect and kill cancer cells. T-VEC is a version of the herpes simplex virus genetically modified to select cancer cells but not healthy cells for infection, while also secreting an immune-boosting protein added to the drug that can strengthen the body’s immune response against melanoma. Over many months, a massive amount of the virus is injected directly into detectable skin tumors, where it replicates inside the tumor cells, causing them to rupture and die. At the same time, the immune-boosting protein in the drug kick-starts the immune system to attack the injected tumors.

    The question remains whether the immune system attacks only the injected tumors or goes on to attack tumors throughout the body, but in the clinical trials, the therapy increased durable response rates (up to six months) for patients with advanced disease, shrinking tumors in about 16 percent of patients. While these benefits are fairly limited, and while the drug has not proven to extend survival or prevent metastases to the organs, T-VEC represents a new avenue for treatment that researchers hope to improve upon significantly. This agent is also being tested in combination with other therapies, including the checkpoint blockade therapies, and appears to enhance their beneficial effects.

    Similar oncolytic viruses are now being tested, with the goal of producing more dramatic results for melanoma patients who have recurrences.

    Radiotherapy
    Radiation, directing X-ray beams at the tumor, is more often used to treat basal or squamous cell carcinoma tumors in certain patients, but it is now also being tested in combination with the checkpoint blockade therapies for advanced melanoma, and like T-VEC, appears to enhance their beneficial effects. Preclinical and early-phase studies suggest that it may synergistically react with these immunotherapies, boosting immune response in several ways: releasing and processing tumor antigens, upregulating cell death receptors, deleting regulatory T-cells and activating other T-cells for attack. Like T-VEC, it may produce both local effects, ridding the primary tumor microenvironment of remaining cancer cells through immune-related clearance, and also stimulate a systemic immune response that helps control distant disease. But more preclinical research must be done to home in on ideal immunotherapy-radiation combinations and learn more about timing and doses.

    One important new use of radiation is in the treatment of oligometastases, limited metastatic tumors that travel from the primary tumor to just one or two distant parts of the body, including organs. By itself, it can be curative at these sites, and combined with systemic therapy it can be even more effective, potentially stopping the cancer from spreading altogether.

    Adoptive Cell Transfer
    The use of white blood cells called tumor-infiltrating lymphocytes (TILs) is another, still experimental, avenue for immunotherapy in advanced melanoma patients. Of special note is a technique from the National Cancer Institute called adoptive cell transfer (ACT), which involves harvesting TILs from the patient’s blood. Scientists identify and isolate the most effective melanoma-killing T cells from these TILs. They then grow them in large numbers in the lab and reinject them into the patient in the hope that they will massively attack the patient’s melanoma cells. The doctors may add high doses of the immunotherapy interleukin-2 to make these tumor-fighting cells mature and multiply. They may also use certain drugs to eliminate immune factors (and even bone marrow) that might inhibit the tumor-fighting cells. (This is called lymphodepletion.) In clinical trials with metastatic melanoma patients who had not responded to previous treatment, the patients’ response rates have been far higher than those seen with chemotherapy.

    In recent trials, total-body irradiation was added to enhance lymphodepletion, and response rates up to 72 percent were observed in 93 patients, with 11 achieving complete remissions lasting 18 to 75 months or more.

    Reduced Roles for Earlier Immunotherapies
    As recently as five years ago, injectable interferon alfa-2b for adjuvant use (intended to prevent recurrence or metastatic spread) in high-risk stage II and stage III patients and interleukin-2 (for stage IV patients) were the only approved immunotherapies for advanced melanoma. However, adjuvant interferon in low-, intermediate- and high-dose regimens (the high-dose regimen is the only one approved in the U.S.) has proven to have little or no effect on patients’ survival, and interleukin-2 has improved survival for an extremely limited percentage of patients. With the success of the revolutionary checkpoint blockade immunotherapies and targeted therapies, high-dose interferon and interleukin-2 have been relegated to backup or complementary roles used after other therapies, to reinforce other therapies or as a treatment arm in clinical trials testing other drugs.

    In 2011, the FDA approved a new subcutaneously injected variation of high-dose interferon alfa-2b called peginterferon alfa-2b (Sylatron®) as an adjuvant therapy to treat stage III melanoma patients. Through pegylation,the process of attaching polyethylene glycol molecules to (or amalgamating them into) a therapeutic agent, this drug may give patients a longer period before recurrence than interferon alfa-2b, but like that earlier drug, has not been proven to extend lives. It is considered a second-line or complementary therapy to the checkpoint blockade immunotherapies and targeted therapies.

  • Targeted Therapy

    Targeted therapies, among the most revolutionary treatments for advanced melanoma, use drugs or other substances to identify and attack specific types of cancer cells, or to block the action of certain genes, enzymes, proteins or other molecules that promote the growth and spread of cancer cells. This allows the cancerous cells to be treated without killing healthy cells.

    In the past decade, there has been a wave of notable successes in targeted melanoma therapy. The first was vemurafenib (Zelboraf®), FDA-approved in 2011, a drug taken by mouth that inhibits a defective (mutated) version of a gene called BRAF. BRAF produces a protein that normally regulates skin cells, causing them to multiply only when growth is needed. However, specific mutations in BRAF called v600E (found in about half of all melanoma patients), and less frequently, two other defective versions of BRAF called v600K and v600D, produce an abnormal version of the protein that stays switched on. This leads to out-of-control cellular growth, i.e., cancer.

    Vemurafenib can bind to the defective protein and deactivate it. Studies have shown that it produces rapid, striking antitumor activity in patients with BRAF V600E- and V600K-mutated stage IV melanoma, delaying disease progression and increasing patients’ survival compared with standard chemotherapy (median 13.6 months’ survival for vemurafenib patients vs. 9.7 months for chemotherapy patients). And some patients go much longer before recurrence. However, most patients eventually develop resistance to the treatment, and the melanoma starts to grow and advance again.

    To delay resistance and increase survival time, scientists next developed two other targeted treatments, one directed at BRAF and another targeting a related molecule called MEK. The FDA approved the BRAF inhibitor, dabrafenib (Taflinar®), and the MEK inhibitor, trametinib (Mekinist®), both taken by mouth, in 2013. Like vemurafenib, these newer targeted therapies can be used only in patients who have the defective BRAF gene.

    Used in combination, dabrafenib and trametinib produce more rapid responses and higher response rates in metastatic melanoma patients than either agent or vemurafenib alone. The principle behind this combination therapy is that even when the BRAF inhibitor meets with resistance in inhibiting melanoma, the MEK inhibitor further slows disease progression by blocking MEK, at least delaying the melanoma’s advance.

    In 2014, the FDA approved the use of combination dabrafenib and trametinib for patients who have inoperable or metastatic melanoma with a BRAF V600E or V600K mutation. Due to superior results, this combination therapy and two newer targeted combination therapies are now generally used in preference to vemurafenib, dabrafenib or trametinib alone. This drug combination has reduced resistance, increased tumor shrinkage and extended the length of time before the melanoma starts growing again, leading to longer survival. Studies show that a remarkable 51 percent of BRAF-mutated stage IV metastatic melanoma patients on combination dabrafenib-trametinib are still alive at two years, with median survival of 25.6 months, vs. 45 percent of patients on dabrafenib alone and 38 percent of patients on vemurafenib alone (median survival 18 months).

    In 2015, the FDA approved a second targeted combination BRAF/MEK inhibitor therapy for advanced melanoma. Combining the established BRAF blocker vemurafenib with a new oral MEK blocker called cobimetinib (Cotellic®), the therapy was approved for stage IV BRAF-mutated patients with melanoma that is inoperable or has metastasized throughout the body. This new combination therapy works similarly to dabrafenib-trametinib. Like dabrafenib, vemurafenib blocks the mutant BRAF gene, while cobimetinib, like trametinib, blocks MEK. By inhibiting these two different parts of the signaling pathway that promotes metastasis, the new combination therapy delays advance of the disease about five months longer on average (12 months vs. seven months) than vemurafenib alone. Patients on this combination therapy also live longer on average than those on vemurafenib alone, with approximately 65 percent of patients alive 17 months after starting treatment, compared with about 50 percent of those taking vemurafenib only.

    In 2018, the FDA approved yet another combination targeted therapy for stage IV inoperable or metastatic melanoma. The therapy combines two new drugs taken by mouth, the BRAF blocker encorafenib (Braftovi) and the MEK blocker binimetinib (Mektovi®), which are used only in combination. The therapy has produced some of the best results ever achieved for stage IV melanoma. As with patients on combination vemurafenib-cobimetinib and dabrafenib-trametinib, those on this therapy have slower disease progression and longer overall survival than those on vemurafenib or dabrafenib alone, while also experiencing fewer serious side effects. 

    This combination therapy was approved based on results from the phase 3 COLUMBUS trial, which demonstrated that it doubled median progression-free survival (PFS) compared to vemurafenib alone (14.9 months versus 7.3 months, respectively), and preliminary results show that it also doubles overall survival (OS) compared with vemurafenib alone (33.6 months versus 16.9 months). PFS for this combination was even slightly better than for vemurafenib-cobimetinib and dabrafenib-trametinib. It is the first targeted treatment to demonstrate over 30 months median OS in a phase 3 trial.

    With all three of these combination therapies producing superior results to vemurafenib or dabrafenib alone, they have become the standard frontline targeted options for treating BRAF-mutant melanoma, although single-drug therapy may still be useful in certain situations. In addition, the checkpoint blockade immunotherapies have become an alternative front-line choice for metastatic melanoma patients, even those with the defective BRAF gene.

    The most common serious side effect of the targeted therapies is the formation of nonmelanoma skin cancers, especially squamous cell carcinomas, most of which are small or superficial and can be treated effectively. Other side effects include fatigue, diarrhea, nausea, vomiting, abdominal pain and arthralgia.

    Also in 2018, the FDA approved the use of combination dabrafenib-trametinib as an adjuvant treatment for patients with BRAF V600E-positive or V600K-positive stage III melanoma following complete removal of the primary tumor. The approval was based on the results of the COMBI-AD trial, the first randomized study ever of combination BRAF-MEK inhibition as a melanoma adjuvant therapy, published in The New England Journal of Medicine. In the study, the combination reduced the risk of disease recurrence or death by 53 percent compared with placebo for patients with BRAF-mutant stage III melanoma. After a median follow-up of 2.8 years, the three-year recurrence-free survival rate with dabrafenib-trametinib was 58 percent compared with 39 percent for the placebo arm. Early data on overall survival showed that 86 percent of patients in the combination arm were still alive at three years, versus 77 percent in the placebo arm.

    Adjuvant therapies are strategies that enhance the effectiveness of a primary treatment such as surgery, with the goal of delaying recurrence and extending overall survival. The hope is that by using this medicine before the cancer reaches stage IV, spreading throughout the body, it will provide even greater benefits for patients and save more lives.

  • BRAF and MEK Inhibitors versus Immune Checkpoint Blockade Therapies

    With the rapid evolution of immunotherapies and targeted therapies for advanced melanoma in the past seven years, the choice of frontline treatment has continually shifted. With FDA approval of the BRAF inhibitor vemurafenib (Zelboraf®) in 2011, targeted anti-BRAF therapy became the standard frontline treatment for stage IV melanoma patients with the defective BRAF gene. For stage IV patients who did not have the defective gene, the checkpoint blockade immunotherapy ipilimumab (Yervoy®), which inhibited the immune checkpoint CTLA-4, became the frontline treatment upon FDA approval in 2011.

    Then, when the combination targeted therapy dabrafenib-trametinib was approved in 2013, proving more effective than either vemurafenib or dabrafenib alone, combination dabrafenib-trametinib came to be accepted as the preferable frontline treatment for patients with the mutant BRAF gene. Ipilimumab remained the first option for those who did not have the mutant gene, and the second-line therapy for patients in whom the targeted therapy failed or stopped working.

    The field shifted again in 2014, when the new PD-1-inhibiting checkpoint blockade therapies pembrolizumab (Keytruda®) and nivolumab (Opdivo®) were approved. Studies soon showed them to be safer and more effective than ipilimumab, and they eventually replaced ipilimumab as the frontline therapy for advanced melanoma patients who did not have the mutant BRAF gene. Then, combination nivolumab-ipilimumab was approved in 2015, proving somewhat more effective than pembrolizumab, nivolumab or ipilimumab alone. However, due to its more serious side effects, the choice of frontline treatment among nivolumab, pembrolizumab and the combination therapy can vary depending on factors such as the patient’s age, extent of disease and overall health. 

    Also in 2014, the FDA approved the targeted combination therapy vemurafenib-cobimetinib (Cotellic®), comparable to the combination targeted therapy dabrafenib-trametinib, adding to patients’ available options. And in 2018, the FDA approved yet a third BRAF-MEK blocker, combining the new BRAF blocker encorafenib (Braftovi) with the new MEK blocker binimetinib (Mektovi®). At the moment, all three combinations are roughly comparable frontline choices for mutant BRAF patients, but the study findings on the benefits and side effects of combination encorafenib-binimetinib were so good that it remains to be seen if this combination might take the lead as the frontline therapy.  

    Recent research has also shown that the approved checkpoint blockade therapies pembrolizumab, nivolumab and combination nivolumab-ipilimumab are all effective whether or not patients have the mutant BRAF gene, and are often more effective than any of the targeted BRAF therapies and may be more effective than the targeted BRAF therapies at achieving durable survival. 

    Depending on their situation and personal preferences, advanced melanoma patients now most often choose from among six treatments as their frontline therapy: the single agent checkpoint blockade therapies nivolumab or pembrolizumab, combined nivolumab-ipilimumab or, for patients with the mutated BRAF gene, the targeted combination therapies dabrafenib-trametinib, vemurafenib-cobimetinib or encorafenib-binimetinib. A variety of factors may influence the decision. For example, the targeted therapies tend to begin working faster, often eliminating many or all tumors at a rapid pace. Thus, if the patient has the mutant BRAF gene and needs rapid elimination of tumors to survive, the combination targeted therapies might be the frontline choice.

    However, this type of therapy may begin to fail sooner than the immunotherapies, so if rapid elimination of tumors is not as important, the patient and physician might opt for one of the checkpoint blockade immunotherapies, which offer the best chance of long-term survival. The most effective of all these therapies at present is combination nivolumab-ipilimumab (by a small margin over pembrolizumab or nivolumab alone), which may make it the first choice, particularly if rapid response is needed in a patient with advanced melanoma. However, it is a riskier therapy than either pembrolizumab or nivolumab alone, with a greater chance of serious side effects that might stop the therapy, so for older or frailer patients with poorer immune systems, either pembrolizumab or nivolumab alone might be the first choice.

    Ultimately, of course, making these decisions remains up to you and your doctor, based on your health and other factors. The good news is that today, if your first therapy doesn’t work or stops working, other approved, effective therapies now exist that often can be tried next. Researchers are continually homing in on which combinations, methods and sequences are most suitable to slow or eliminate melanoma most effectively, maintain the best possible quality of life for patients and extend their lives as long as possible. Many other new approaches are also on the horizon, currently in active laboratory study or clinical trials that you can look into. The hope is to turn metastatic melanoma into a manageable or even curable condition.

  • Chemotherapy

    A number of chemotherapy drugs active in fighting cancer cells have been used to treat melanoma, either one at a time or in combination. However, with new immunotherapies and targeted therapies producing much better results, the chemotherapies have been phased out as frontline treatments. They are sometimes used to supplement the other treatments. To date, dacarbazine (DTIC), given by intravenous infusion, is the only chemotherapy approved for melanoma by the U.S. Food and Drug Administration (FDA). DTIC may be combined with the chemotherapies carmustin (BCNU) and tamoxifen, or with cisplatin and vinblastine. Temozolomide, an oral drug closely resembling DTIC, is FDA-approved for brain cancers but also used off-label (without specific FDA approval) for melanomas that have spread to the brain or nervous system.

  • Radiation Therapy

    Radiation, directing high-energy X-ray beams at the cancer cells to destroy them, is being combined experimentally with some of the medications used for advanced melanoma, and results so far are promising. External beam radiation therapy (EBRT) focuses radiation from outside the body on the skin tumor.

    While rarely used to treat a primary melanoma tumor, radiation therapy can also sometimes be used after surgery to lower the chance of recurrence in a site where lymph nodes have been removed, especially if many nodes were cancerous. In addition, it may be used on occasion to help treat melanoma that has come back after surgery in the skin or lymph nodes. Radiation therapy has a definite role in treating spread of melanoma to the brain and in relieving symptoms and pain in specific areas where the melanoma has already spread, by shrinking or slowing the tumor’s growth.

    Radiation therapy is now being used in combination with immune checkpoint inhibitors, and is producing very promising results both by enhancing the antitumor immune response to those drugs and by reducing tumor size so the drugs can work more effectively.

  • Clinical Trials

    Many patients, especially those with advanced disease, participate in clinical trials to obtain new treatments that may be more effective than standard therapy but are still experimental and not generally available.

    Patients who have stage III and IV melanoma might consider enrolling in a clinical trial of a new or experimental treatment. There are risks involved in enrolling in a clinical trial, but there can be benefits as well. Discuss the possibilities with your doctor. More treatment possibilities exist than ever before, giving ever greater hope to people with advanced melanoma.

Next Steps: Improving Long-Term Survival

The advances in understanding melanoma and the immune system have set the stage for continual improvements in the treatment of advanced disease. A substantial proportion of patients have already derived significant long-term benefits and are now living years longer than in the past.

The next goals will be to determine which combinations and methods are most suitable to shrink or even eliminate melanoma most effectively, maintain the best possible quality of life for patients and extend patients’ lives as long as possible. Many other novel approaches are also on the horizon, currently either in active laboratory study or clinical trials; the hope is to turn metastatic melanoma from a deadly disease into a manageable chronic condition.

Medical Reviewer: Susan Swetter, MD, Stanford University Medical Center and Cancer Institute