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Unresectable or metastatic melanoma refers to tumors that cannot be removed surgically or that have spread to distant sites in the body. Melanoma might be unresectable for a number of reasons, including the location or the patient's overall health or preference.

Unresectable melanoma includes some stage III lesions, whereas distant metastatic lesions are all stage IV. Recent progress in drug therapy for melanoma has helped more patients with advanced melanoma live longer, more productive lives.

Metastatic melanoma may be limited to a few sites or be widespread (disseminated). Surgery remains an option for many patients with limited metastatic melanoma. If the disease has spread to many distant sites, drug therapy usually is the first choice.

Basic Approach to Treatment

Historically, surgery has had a limited role in treating unresectable/metastatic melanoma as compared with early-stage disease. Chemotherapy formed the basis of treatment for most patients. Over the past two decades, newer, non-chemotherapy drugs have emerged to take the place of conventional chemotherapy. Based on better understanding of the biology of cancer, the newer drugs are more effective and generally better tolerated than chemotherapy.

In some cases, drug therapy can shrink unresectable tumors and make surgery possible. When surgery is possible for limited metastatic melanoma, a patient might also receive drug treatment after surgery, which is called adjuvant therapy.

Radiation therapy for melanoma is used primarily to relieve pain and other cancer-related symptoms.

Targeted Therapy

As the name suggests, targeted drugs home in on, or target, specific processes involved in cancer formation and progression. In the case of melanoma, the available targeted therapies are specific for an abnormality in a gene called BRAF. As many as half of all melanomas have a BRAF mutation.

Two drugs are used in combination to block an abnormal protein produced by a mutated BRAF gene. Three different two-drug combinations have been approved in the U.S. to treat BRAF-positive melanoma: dabrafenib (Tafinlar)/trametinib (Mekinist), vemurafenib (Zelboraf)/cobimetinib (Cotellic), and encorafenib (Braftovi)/binimetinib (Mektovi). Rarely is an individual anti-BRAF drug used by itself.

Immune Checkpoint Inhibitors (ICIs)

ICIs are the most widely used drugs for initial treatment of advanced melanoma. Improved survival in unresectable/metastatic melanoma has a direct correlation with increased use of ICIs, often called immunotherapy. The drugs have improved survival in melanomas with and without BRAF mutations.

The term "immune checkpoint inhibitor" comes from the drugs' mechanism of action. The human immune system, the body's natural defenses against disease, has a series of checks and balances (checkpoints) that allow the system to protect the body but also turn down or brake the system so that it doesn't destroy normal cells and tissue. Melanoma and other types of cancer have the ability to "put the brakes on" indefinitely. ICIs block melanoma's braking effect, allowing the immune system to respond more aggressively to the cancer.

Two types of ICIs are available to treat melanoma: the PD-1 inhibitors pembrolizumab (Keytruda) and nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy). PD-1 and CTLA-4 refer to the specific immune system checkpoints where the drugs focus their anticancer activity.

Pembrolizumab and nivolumab are widely used as initial treatment for advanced melanoma. Nivolumab also is approved for use in combination with ipilimumab. Ipilimumab can be used by itself but more often is used in combination with nivolumab. Patients who respond to ICIs often have prolonged responses -- substantially longer than with chemotherapy or targeted therapies.

Injection Therapy

Occasionally, a doctor may inject a cancer drug directly into a melanoma, a treatment called intralesional therapy. This type of treatment typically is used to shrink a tumor before surgery or to relieve symptoms. A drug called T-VEC (Imlygic) is approved for direct injection.

Clinical Trials

Although newer therapies have improved survival and quality of life in melanoma, many patients do not benefit from the treatment, or the benefits are not long lasting. Enrollment in a clinical trial gives patients access to therapies that may offer better outcomes.

Numerous planned and ongoing trials are evaluating drug combinations, as well as new and novel approaches to treatment. Ask your doctor whether a clinical trial might be the best option for you.

Read previous installments in this series:

For Your Patients: What Is Melanoma?

For Your Patients: Is What You're Seeing Harmless or Is It Melanoma?

For Your Patients: Is It Melanoma or Something Else?

For Your Patients: What to Know about Treating Early-Stage Melanoma

"Medical Journeys" is a set of clinical resources reviewed by doctors, meant for physicians and other healthcare professionals as well as the patients they serve. Each episode of this 12-part journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.