Melanoma treatment options

Surgery

Surgery is the first treatment step for most melanomas, and often the only treatment necessary when it is an early-stage melanoma. Surgery is also used for lymph node evaluation and dissection, as well as for selected patients with advanced melanoma when the tumour(s) can be resected (surgically removed).

Surgery for early-stage melanoma

Wide Local Excision (WLE)

Purpose: To remove any of the primary tumour that may remain after a biopsy.

What Is It? WLE is the standard surgical procedure to remove the primary tumour on the skin.

The surgeon removes the tumour, including the biopsy site, as well as a surrounding area of normal-appearing skin and underlying subcutaneous tissue, to ensure the whole tumour has been removed.

Side Effects: Surgery for primary melanoma involves the removal of skin which can leave a scar.

Other side effects can include infection, numbness, and swelling.

Importantly, if a sentinel lymph node biopsy is needed, it is often performed at the same time as the WLE.

Skin Grafting

Purpose: To replace the skin where the primary tumour has been removed when the amount of tissue removed is too great to allow the wound to be closed with stitches or staples.

What Is It? Skin grafting is a procedure usually performed by a surgical oncologist or a plastic surgeon. Skin from another part of the body is used to cover the site of the surgical removal of the tumour. The skin used to cover the incision is usually taken from areas of the body that are typically hidden or covered with clothing.

Side Effects: Side effects from skin grafting may include bleeding, infection, graft failure, poor healing, altered sensation, altered hair growth, and contraction of the graft leading to decreased mobility. Rarely, the entire graft can be lost, leading to either very delayed healing or the need for further surgery.

Surgery for stage III melanoma

Sentinel Lymph Node Biopsy (SLNB)

A Sentinel Lymph Node Biopsy (SLNB) is performed by a surgeon to check if the melanoma has spread to the lymph nodes.

The sentinel lymph node(s) is the most likely to contain melanoma, so it is identified and removed for evaluation.

SLNB is a surgical procedure in which only the sentinel lymph node(s) – the very first lymph node(s) to receive drainage from the tumour area – is removed and the biopsy is tested.

Lymphatic mapping (where a blue dye is injected into the skin around the tumour, along with a small amount of radioactive substance) is performed in conjunction with SLNB. The dye gives the surgeon a visual reference to find the sentinel lymph node(s).

If your melanoma has spread to several lymph nodes, then removing all lymph nodes in that region may be recommended.

Lymph Node Dissection

For some patients, whose melanoma has spread to several lymph nodes, removing all the lymph nodes in that region may be recommended.

Lymph node dissection can be explained as surgery to remove all regional lymph nodes from the area where cancerous lymph nodes were found.

Surgery for stage IV melanoma

Patients with only one or a few sites of metastatic melanoma may be candidates for surgery to remove all known disease.

Surgery may also be considered to relieve symptoms.

Surgery for metastatic melanoma may also be an option when treatment with drug therapy has led to dramatic shrinkage, but one or a few relatively small areas of disease remain.

Systemic drug therapy

While historical options used in the treatment of melanoma were not very effective, modern drug therapies are known to be effective in a significant percentage of patients. Treatment can often involve more than one type of treatment.

The following terms are used to describe the order of treatments which are given: 

• Neo-adjuvant treatment is what is given before primary treatment—in melanoma, primary treatment is generally surgery—to shrink tumours. 
• Primary treatment is the main treatment to remove cancer. 
• Adjuvant treatment is given after primary treatment to kill any remaining cancer cells, including ones that can’t be easily seen.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs to identify and stop the action of molecules that are key to the growth of cancer cells. Targeted therapy ‘targets’ the changes in cancer cells that help them grow, divide, and spread, with minimal effect on normal cells. Most side effects, or effects on other cells as a result of the therapy, will stop when the treatment stops.

Research has identified several molecular pathways and mutated genes in melanoma, such as the BRAF, C-KIT, and NRAS mutations.

Targeted therapies benefit patients whose melanoma cells have specific mutations and can block or turn off signals that make the melanoma cell grow, multiple, or it can give it instructions to destroy itself.

BRAF mutations occur in about 40% of all melanoma patients. These mutations are known to produce altered BRAF and MEK proteins that help melanoma cells grow. If a patient’s melanoma has the BRAF mutation, a treatment that targets the BRAF proteins (BRAF inhibitors) or the MEK proteins (MEK inhibitors) can be helpful. Patients who do not have this mutation, also known as BRAF wildtype patients, do not benefit from medications targeting this pathway.

Using BRAF + MEK inhibitor together to treat advanced melanoma, has been shown to be more effective and interestingly has less side effects than a BRAF inhibitor alone. There are 3 different types of this combination therapy and no head-to-head study to compare them. All are considered to be as effective as each other in terms of activity, but they differ in terms of how they are tolerated and their side effect profile. All of them are taken as an oral pill.

Current targeted therapy combinations approved for use in Australia include:

• Dabrafenib + trametinib (Also known as Tafinlar + Mekinist)
• Vemurafenib + cobimetinib (Also known as Zelboraf + Cotellic)
• Encorafenib + binimetinib (Also known as Braftovi + Mektovi)

Patients with cancer symptoms like pain and/or fatigue will often notice a fast improvement of their symptoms soon after commencing treatment. If side effects from one BRAF/MEK combination aren’t tolerated, patients may switch to a different BRAF/MEK combination.

A patient with a BRAF mutation may be treated with an immunotherapy first and then a targeted therapy second, or vice versa. In situations where a patients treatment plan could consist of both a targeted therapy and an immunotherapy, sequencing becomes important. This should be discussed between a patient and their treating team, to weigh up the likelihood of a higher response rate with targeted therapy versus the likelihood of a durable response which can be higher with immunotherapy. It is a complex decision that will also require a trade-off of likely side effects, and whether any of them include permanent side effects.

Immunotherapy

The immune system allows the body to distinguish its own healthy cells from abnormal or foreign cells and organisms. Foreign invaders include viruses, bacteria, and other disease-causing organisms. For example, the immune system will usually recognise a cell that is infected with a virus, and that’s why the body can recover from a common cold, but the immune system has a more challenging time targeting cancer cells. Sometimes the immune system doesn’t see the cancer cells as foreign because the cells aren’t different enough from normal cells. Sometimes the cancer cells create a clever disguise, similar to an invisibility cloak, that means the immune system doesn’t recognise them. Immunotherapy works by helping your body’s immune system to notice these cancer cells and strengthen its response so that it can destroy them.

Some types of immunotherapy are also called biologic therapy or biotherapy, or immuno-oncology (IO).

Types of Immunotherapy for Melanoma

The main types of immunotherapy used to treat advanced melanoma include: 

Immune Checkpoint Inhibitors

These therapies are monoclonal antibodies such as anti-CTLA4 and PD-1 antibodies that are designed to target receptors on the surface of immune cells to either activate or inhibit their function. They act by reactivating and supercharging the immune system, allowing immune cells to recognise and attack the cancer cells. The downside to this approach is that it is non-specific, which means that immune-related (or auto-immune) side effects are expected. The frequency and impact of these side effects can vary greatly, so require regular communication between the person receiving treatment, and their healthcare team. Most effects can be managed with steroids, but some can be more serious, and some can leave permanent impact.

Ipilumumab was the first of the immunotherapy therapies. It is an anti-CTLA4 antibody which is now known as the first generation of checkpoint inhibitors. Commonly referred to as “ipi”, it is not usually used on its own anymore, but more commonly in combination with other checkpoint inhibitors.

Other immunotherapies include PD-1 inhibitors which have demonstrated benefit in all advanced melanoma patients regardless of their BRAF status. PD-1 inhibitors can be used alone, or in combination with ipilumumab. Approved PD-1 inhibitors include pembroluzimab (commonly called “pembro”) and nivolumab (commonly called “nivo”).

PD-L1 refers to Programmed Death-Ligand 1. In many melanoma cells, PD-L1 is expressed and attaches itself to immune cells throughout the body. It acts as an ‘off switch’, so that the immune system doesn’t recognise the melanoma cell as abnormal, and therefore does not destroy it. PD-1 inhibitor drugs block this binding, meaning the melanoma cells can no longer hide from the body’s immune system, and it can then recognise and attack the cancer cells.

Cellular Therapies

Cellular therapies use a patient’s own immune cells that have been removed from the body, processed in a lab and reprogrammed to be more effective fighting cancer, and then re-infused into the patient’s body.

These types of therapies include tumour-infiltrating lymphocytes (“TILs”) and chimeric antigen receptor (CAR) T-cell therapy. These therapies are not widely available in Australia and their effectiveness against melanoma continues to be measured in clinical trials. 

Other targets and future treatments

There are several other pathways and targets being explored in clinical trials for the treatment of melanoma.

Radiation therapy

Radiation therapy is also called radiotherapy.

Radiation therapy uses ionising energy (high-energy radiation) to damage the DNA of cancer cells, that ultimately leads to these cancer cells dying. The radiation injures both normal cells and cancer cells. However, normal cells can repair themselves while cancer cells can’t and die after treatment.

Radiation therapy can be used in high-risk or advanced cases of melanoma where surgery may be complicated or not possible. Although radiation rarely cures advanced melanoma, it can frequently shrink tumours that cause discomfort. That is, radiation therapy is primarily used to lessen symptoms in patients with advanced melanoma.

More recently, radiation therapy is used in combination with immunotherapy to increase the effectiveness of the immunotherapy. This is called an abscopal effect and is still being studied.

The radiation oncologist makes decisions about the radiotherapy dose and technique, after consulting with the surgeons and medical oncologists. Radiation therapy is a highly technical and precise treatment. It can be delivered by different radiation therapy machines and techniques. You can receive treatment in a hospital or at a treatment centre, usually as an outpatient.

Stage III patients

Radiation therapy may be used after surgery, for patients with multiple or large cancerous nodes, to prevent the tumours from returning at that site.

Radiation therapy improves the ability to control the recurrence of cancer at the site where it was removed, in patients with high-risk features. However, it has not been shown to reduce the risk of distant disease (cancer that appears in another area of the body), or overall survival. For this reason, immunotherapy and targeted therapy drugs are used more often in Stage III patients.

Stage IV patients

Radiation therapy for Stage IV patients is primarily used to relieve symptoms by shrinking the tumours. It’s typically used in patients whose melanoma has spread to the bones or to parts of the body that make it difficult to surgically remove the tumour.

Importantly, where there is a single tumour or only a few sites, higher dose radiation therapy (sometimes delivered as stereotactic radiotherapy) may be used in combination with newer medical treatments with the aim to prolong survival.

Stage IV patients with brain metastases

In the case of brain metastases, radiation therapy may be a primary treatment, with the goal of preventing further growth of tumours even in patients without symptoms. This is usually done with stereotactic radiotherapy techniques. It may also be used with a goal to relieve symptoms such as partial paralysis, headaches, and seizures. To deliver the treatment, CT scans and MRIs are used to pinpoint tumour location(s).