The process typically begins (and for the most fortunate patients, ends) with surgical removal of the tumor. This procedure generally takes place at the doctor’s office under local anesthesia. Melanoma caught early is highly curable, with a five-year survival rate of 99 percent, according to the American Cancer Society. (1) But if cancer cells have spread to the lymph nodes or beyond, surgery alone is not enough. Until recent years, metastatic melanoma had an extremely daunting prognosis. It remains a tough cancer to beat. But advances in areas such as immunotherapy and targeted therapy have transformed the treatment of melanoma, offering tremendous hope. Even patients with the most severe cases are prolonging their lives by months or years, and some are even going into long-term remission. Depending on several aspects (including stage, molecular features of the tumor, type of therapy used), the five-year survival rate for stage 4 melanoma reaches up to 30 percent. As therapies continue to be developed, those numbers may continue to increase. (1)
Surgical Procedures Have Improved
For most patients, the first step in treating melanoma is usually cutting out (excising) the tumor. Doctors also remove an area of healthy-looking tissue around the cancer, the “safety margin.” A pathologist looks at this tissue under a microscope to make sure there are no stray cancer cells invading through the margin. A decade ago, margins of 3 to 5 centimeters were standard. Today, thanks to surgical advances, doctors set margins at a maximum of 2 centimeters, even for the most advanced cases. The result is fewer stitches, smaller scars, and an easier recovery. Some doctors who are looking to minimize the loss of healthy tissue even more may turn to Mohs micrographic surgery, a method more commonly used for other types of skin cancer. A Mohs surgeon will remove the tumor one thin layer of skin at a time, scrutinizing each section under a microscope for cancer cells before excising to the next. The surgery is over as soon as a sample is cancer-free. The development of sophisticated new stains that highlight melanoma cells in tissue samples helps ensure Mohs surgeons don’t miss any. (2) If cancer cells have spread from the tumor to nearby lymph nodes — clusters of bean-shaped structures located throughout the body that contain white blood cells — a surgeon may choose to remove them. This procedure is called a full lymph node dissection. Some doctors opt not to include the procedure as a standard treatment. Their reasoning is that not only can lymph node removal cause problematic side effects, but it has not been proven to boost survival. In one study, researchers at Memorial Sloan Kettering Cancer Center in New York City looked at 2,000 patients who tested positive for melanoma in their sentinel lymph node — the one closest to the tumor. The researchers found that immediately removing the remaining lymph nodes did not improve survival compared with a watch-and-wait approach. (3) Recent research suggests that a combination of surgery and immunotherapy — drug cocktails that reduce the ability of cancer cells to reproduce in the body — may lead to the best outcomes for certain patients. Which treatment to administer first is an area of ongoing research. One study from 2022, for example, found that once melanoma has spread to lymph nodes, immunotherapy followed by surgery may be more beneficial than surgery followed by immunotherapy. (8)
Immunotherapy Is Changing the Game
While chemotherapy was once the go-to treatment for metastatic cancer, newer approaches have proven to be so much more effective that chemo is now only very rarely used in cutaneous melanoma patients. Immunotherapy has changed the way oncologists battle advanced melanoma as well, allowing them to harness the power of the body’s own immune system to fight disease. A type of immunotherapy called checkpoint blockade therapy — or checkpoint inhibitor therapy — is significantly extending the lives of many people with stage 2, stage 3, and stage 4 melanomas. The Food and Drug Administration (FDA) has approved multiple such drugs since 2011. Two drugs approved in 2014, pembrolizumab (Keytruda) and nivolumab (Opdivo), have become front-line treatments (either alone or in combination with other drugs) for metastatic melanoma. Both work by blocking the action of a molecule called PD-1 (programmed death-1), which normally keeps the immune system’s T cells in check. Once freed from the cancer-imposed stymieing effects of PD-1, the T cells attack the cancer. A study that followed 655 advanced melanoma patients on pembrolizumab showed how effective these drugs can be. The average survival was 23 months, and 40 percent of patients were alive three years after starting treatment, with 85 patients becoming and remaining cancer-free. (4) Researchers are finding out that, despite an increased chance of serious side effects, combining different checkpoint blockade therapies may further increase the number of patients who derive a meaningful benefit. A study involving patients treated with both nivolumab and ipilimumab (Yervoy) found that 63 percent had survived for three years or longer. (5) A subsequent study from 2021 looked at these same patients after 6.5 years and found that 34 percent of patients who received the combination therapy and 29 percent of patients who received nivolumab alone were still alive. (9) While highly effective, this combination does have more side effects — related to activating the immune system and causing inflammation elsewhere in the body — than nivolumab alone. Some of these side effects can be reduced by adjusting the dosing schedule without impacting its effectiveness. (10) Most recently, another combination immunotherapy (nivolumab and relatlamib) showed improved rates of survival in patients with metastatic melanoma when compared to nivolumab alone. Importantly, this combination has a lower rate of side effects and thus may be suitable for some patients. (11) Therapeutics alone show great promise for patients with metastatic melanoma, but several studies suggest it’s best to use them in combination with surgery in those with high-risk primary tumors. In those patients, removal of the involved lymph nodes or isolated metastatic lesions — along with immunotherapy — increases the chances for remaining melanoma-free. (12,13) RELATED: Cancer: What Are the Treatment Options for Me?
Targeted Drugs Exploit Mutations in Melanomas
A new generation of melanoma drugs works by targeting mutations (DNA defects) in melanoma cells, shrinking tumors or slowing their growth. About half of all melanomas have mutations (DNA defects) in the BRAF gene that cause out-of-control cellular growth. The FDA has approved three oral combination therapies targeting this mutation, called BRAF and MEK inhibitors. Both types of inhibitors work by binding to defective proteins that promote cancer growth and deactivating them, slowing disease progression and helping patients live longer. In 2013, the FDA approved a combination therapy of BRAF inhibitor dabrafenib (Tafinlar) and MEK inhibitor trametinib (Mekinist). This combination showed prolonged progression-free survival in patients with the BRAF gene and was superior to using BRAF inhibition alone (6). Since then, this combination of drugs has become a frontline treatment option for metastatic melanoma with the BRAF mutation. In a recent study, 51 percent of patients with BRAF-mutant cancer who took both drugs were still alive at two years, with a median survival of 25.6 months. Subsequently, additional combinations of BRAF and MEK inhibitors, including vemurafenib (Zelboraf) with cobimetinib (Cotellic) — and encorafenib (Braftovi) with binimetinib (Mektovi) — were found to be effective and approved by the FDA in 2015 and 2018, respectively. While all BRAF-MEK inhibitors produce similar results, they differ in their side effects. The choice of drug combination is largely guided by this factor, according to the Melanoma Research Alliance. The FDA has also now approved combination BRAF-MEK inhibition for treatment of BRAF-mutated melanoma following surgery. (14)
