Melanoma

Advances in Treatment Offer More Ways to Move Forward

New therapies for treating melanoma continue to be introduced, offering many people hope for a better outcome. Research is also ongoing in clinical trials to find even more options to treat and cure melanoma. To develop a treatment plan, your doctor will take into account the size and location of the tumor, its genetic mutations and the stage of the melanoma.

You’ll work closely with your doctor to develop the plan, providing input about things that are important to you. Together, you will define the goals of treatment and discuss your expectations for quality of life.

About Cancer Treatment

It is common to have more than one type of treatment for melanoma. Your treatments will be either local or systemic (involving drug therapy) or a combination (see Figures 1 and 2). Local treatments target specific areas of the body and include surgery and sometimes radiation therapy. Some can also be injected into a lesion or applied topically to the skin close to a melanoma.

Systemic treatments, including drug therapies such as targeted therapy, immunotherapy and chemotherapy, travel throughout your body. An important goal of systemic therapy is to destroy melanoma cells that may be hiding in other organs of the body, such as the liver, lungs, bones or brain. These hidden cancer cells, called micrometastases, are usually too small to detect with laboratory testing or imaging studies.

Drug therapies can be given orally or intravenously (IV) through a vein in your arm or through an implanted infusion port. A port is surgically inserted under the skin in the upper chest area or arm to gain easy access to veins.

Treatments are described according to when they’re given. Standard of care refers to the best treatment known. Neoadjuvant treatment is given before surgery to shrink a tumor so it can be more easily or safely removed with surgery. Treatment given after surgery is adjuvant therapy. Treatment may be considered first line or second line. First-line therapy is the first treatment given. Second-line therapy is given when the first-line therapy doesn’t work or is no longer effective. Following are descriptions of common treatment options.

 

Surgery

Surgery is usually the first treatment used for local and regional melanomas and is also used for some metastatic melanomas. Often, surgery is the only treatment needed. Surgical removal, or excision, of a melanoma is known as a wide excision. It is used to remove the melanoma and an additional portion of normal-looking tissue, which is called a surgical margin (see Figure 2). The thicker the melanoma is, the larger the surgical margin needed. The tissue removed from the margin will be carefully examined by a pathologist under a microscope to determine if any cancer cells remain. More surgery may be needed if the margins contain cancer cells.

A lymph node dissection is a type of surgery that is sometimes performed to remove lymph nodes in the region after a biopsy if pathology results show a melanoma spread (metastasis) in the sentinel lymph node. At the end of the procedure, the surgeon will likely place drains into the area to collect any blood or fluid from the region where the lymph nodes were removed. The incision will then be closed, and the wound will be covered by a dressing. Your health care team will give you information for incision and drain care, if applicable.

 

Drug Therapy

Various types of anticancer medications are used to destroy cancer cells, prevent progression or slow their growth. The most widely used drug therapies for melanoma are targeted therapy, immunotherapy and chemotherapy.

Targeted therapy is treatment with systemic drugs that stop cancer from growing by in-terfering with specific molecules involved in tumor growth and progression. For example, some melanomas may have mutations (abnormalities) in the BRAF gene, and a type of targeted therapy known as a BRAF inhibitor can be used to treat melanomas with this mutation. BRAF inhibitors are approved for melanomas that have a V600E or V600K mutation in the BRAF gene.

Another target is the MEK protein. Drugs that block MEK proteins are called MEK inhibitors and can also be used to treat melanomas with BRAF mutations to increase the shrinkage of the tumor.

For patients with a BRAF mutation, doctors will likely prescribe a combination of BRAF and MEK inhibitor. Research has found the combination helps shrink tumors better when used together than separately.

Another mutation found in some melanomas is the NTRK gene. The treatment approved for this mutation is considered tumor-agnostic because it is approved to treat the NTRK fusion regardless of the type of cancer or where it is in the body.

Targeted therapies, which are taken orally, may be used to treat both Stage III and Stage IV melanomas. Some may be given in combination with other targeted therapies or types of immunotherapy.

Research is ongoing to find treatments effective against other mutations found in melanoma, particularly in the KIT, NRAS and NF-1 genes.

 

 

Immunotherapy uses the body’s immune system to find and attack cancer (see Figure 4). Immunotherapy may be used as local or systemic therapy, as adjuvant therapy or as primary treatment for melanomas that can’t be removed surgically. The immunotherapies approved by the U.S. Food and Drug Administration for melanoma include monoclonal antibodies (mAbs) such as immune checkpoint inhibitors, cytokines, immunomodulators and oncolytic viruses.

Antibodies (a type of protein) are the body’s natural way of tagging a specific antigen (foreign substance). They bind to the antigen, which allows the rest of the immune system to recognize the antigen as foreign and target it for destruction. A monoclonal antibody (mAb) is a type of protein made in the laboratory that can bind to substances in the body, including cancer cells. A mAb is made to bind to only one substance. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells. The mABs are designed to target specific tumor targets, such as antigens or other proteins found on the cancer cell, and can work in different ways, including flagging targeted cancer cells for destruction, blocking growth signals and receptors, and delivering other therapeutic agents directly to targeted cancer cells.

Immune checkpoint inhibitors are a type of mAb that prevent the immune system from slowing down, which allows the immune cells to continue fighting the cancer. The immune checkpoint inhibitors are monoclonal antibodies that block the receptors of PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death-ligand 1) and CTLA-4 (cytotoxic lymphocyte antigen 4), and thereby inhibit their activating signal to the cell. PD-1 is found on the surface of cells of the immune system and cancer. Normally, when these proteins interact, the immune system does not recognize the melanoma cells as a foreign invader and shuts down. When CTLA-4 or PD-L1 combine with various proteins, they signal to the immune system also to slow down. Anti-CTLA-4 or anti-PD-1 antibodies allow T-cells to continue fighting cancer cells instead of shutting down.

Cytokines are substances secreted by certain cells of the immune system that boost the whole immune system. They can be used alone or in combination with other treatments to produce increased and longer-lasting immune responses. Cytokines aid in immune cell communication and play a big role in the full activation of an immune response. This approach works by introducing large amounts of laboratory-made cytokines to the immune system to promote nonspecific immune responses as a systemic therapy.

  1. Interferons boost the ability of certain immune cells to attack cancer cells. They may be given as adjuvant therapy (given after primary treatment).
  2. Interleukins help control the activation of certain immune cells.

Immunomodulatory drugs may stimulate or slow down the immune system in indirect ways. They may boost the immune system and the effects of other therapies on the tumor and the tumor microenvironment; slow or stop the growth of the tumor and its blood vessel formation; improve the bone marrow microenvironment; or have an anti-inflammatory effect, slowing the growth of the cancer. They are generally considered systemic treatments, but some may be given directly into the tumor.

Oncolytic virus immunotherapy uses viruses that directly infect tumor cells to cause an immune response. It is typically given as a local treatment by injection directly into the tumor. One oncolytic virus uses a weakened version of the herpes simplex virus. The virus targets melanoma cells, infects them and duplicates itself continuously within the cell until it ruptures. This rupture kills the cell and promotes an overall immune boost.

 

 

Chemotherapy treatment may consist of a single drug, a combination given at the same time or drugs given one after another. Chemotherapy may be used alone or with other forms of treatment. It can be used to treat advanced melanoma, but today it is not used often as a first-line therapy. It is usually not as effective for melanoma as it is for other types of cancer.

Isolated limb chemotherapy, either isolated limb perfusion or isolated limb infusion, is a procedure to place chemotherapy directly into a limb when a patient has numerous tumors on the leg or arm. During the procedure, a surgeon temporarily stops the flow of blood in the artery and vein to and from the limb using a tourniquet around the limb. Heated chemotherapy drugs travel through a tube directly into the bloodstream of the limb and are circulated for a certain period. The drugs go in one tube and come back out of the limb through the other. The tourniquet keeps the drugs from leaving the limb and going into the rest of the body. At the end of the procedure, any remnants of the drugs are flushed from the limb.

Radiation Therapy

Radiation therapy uses high-energy radiation to destroy cancer cells and shrink tumors. It is often given as external-beam radiation therapy, which uses a machine outside the body to send radiation toward the cancer.

Though radiation therapy is not typically used to treat the original melanoma, it may be given to areas where lymph nodes were surgically removed or after surgery to remove the melanoma if the risk of recurrence is considered to be high.

Radiation therapy may also be given to relieve symptoms related to the spread of melanoma, particularly to the bones or brain. When given to the brain, whole-brain radiation therapy or localized stereotactic radiation therapy may be used. Stereotactic radiation is given to a specific area of the body in a high dose.

Clinical Trials

These medical research studies may offer access to leading-edge therapies not yet widely available. Multiple new treatment options are being researched in clinical trials, including targeted therapies that target the MAP kinase pathway; immunotherapies with TIM3 inhibitors, LAG3 inhibitors, OX40 agonists, CD137 agonists, GITR agonists, IDO inhibitors and chimeric antigen receptor T-cell (CAR T-cell) therapy; and vaccines. Ask your doctor if you should consider this valuable option as a first-line treatment or at any other time during your treatment.

 

Medication Adherence is Crucial to Effective Treatment

Today, an increasing number of cancer treatments are oral therapies (pills). People undergoing cancer treatment may prefer the at-home option of oral therapy, but it is important to realize this convenience comes with great responsibility.

Most cancer therapies are designed to maintain a specific level of drugs in your system for a certain time based on your cancer type and stage, your overall health, previous therapies and other factors. Taking the right dose of the right drug at the right time on the right schedule is referred to as medication adherence, and it is very important when taking oral therapies.

If your medications aren’t taken exactly as prescribed, the consequences can be serious, even life-threatening.

Taking your cancer treatment correctly may sound simple, but it requires serious effort and coordination to make it happen. Explore the many tools available to help you stay on track. Set alarms or phone reminders, make a daily medication schedule, ask loved ones to remind you, track medications on a calendar, check out medication trackers online or use smartphone apps.

 

Common Drug Therapies for Melanoma
As of 4/1/2021
Targeted Therapy
dabrafenib (Tafinlar)
trametinib (Mekinist)
vemurafenib (Zelboraf)
Immunotherapy
interferon alfa-2b (Alferon, Intron A, Roferon-A)
interleukin-2 (IL-2) (Aldesleukin, Proleukin)
ipilimumab (Yervoy)
nivolumab (Opdivo)
peginterferon alfa-2b (Sylatron)
pembrolizumab (Keytruda)
talimogene laherparepvec (Imlygic/T-VEC)
Some Possible Combinations
atezolizumab (Tecentriq) with cobimetinib (Cotellic) and vemurafenib (Zelboraf)
binimetinib (Mektovi) and encorafenib (Braftovi)
cobimetinib (Cotellic) and vemurafenib (Zelboraf)
dabrafenib (Tafinlar) and trametinib (Mekinist)
ipilimumab (Yervoy) and nivolumab (Opdivo)
Chemotherapy
dacarbazine (DTIC-Dome)

 

 

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