Melanoma treatment options

Surgery

Surgery is the mainstay of treatment for patients with resectable melanoma.  The term “resectable” means that all detectable cancer can be surgically removed. This includes stage I, II and the majority of stage III melanomas. 

Wide Local Excision (WLE)

The standard surgical procedure used to treat melanoma is a wide local excision (WLE). A wide local excision involves removing the primary melanoma on the skin, as well as a surrounding area of normal tissue, also known as a margin, to maximise the chance of removing all cancerous cells in the area. 

Side effects of a wide local excision could include scarring, bleeding, bruising, pain, infection, numbness and swelling. 

Sentinel Lymph Node Biopsy (SLNB)

A sentinel lymph node biopsy is a surgical procedure where one or more lymph nodes are removed to determine whether cancer cells have spread to them. This provides doctors with important information to help decide if additional treatment is required. 

Lymph nodes are glands located throughout the body that serve as part of our immune system. They collect and filter fluid, picking up any foreign materials, such as cancer cells, viruses or bacteria, and exposing them to immune cells that reside in the lymph nodes. A sentinel lymph node is the first lymph node that a cancer is predicted to spread to. For example, the sentinel lymph node for a melanoma on the leg is usually located in the groin, whereas the sentinel node for a melanoma on the upper is typically in the axilla (armpit).  The need for a sentinel lymph node is determined by the predicted chance of the melanoma spreading beyond where it originated in the skin and is based on factors including thickness of the melanoma. In general, a sentinel lymph node biopsy is usually not performed if the predicted chance of spread to the sentinel nodes is very low. Your individual circumstances are also considered, including your general health and personal preferences. Your surgeon will discuss whether a sentinel lymph node biopsy is recommended for you.  

A sentinel lymph node biopsy is usually performed at the same time as a wide local excision.  The sentinel lymph nodes are located by injecting a coloured dye into the skin around the tumour, which drains via lymphatic vessels into the sentinel lymph nodes, allowing them to be visualised. The identified node(s) are removed and analysed by a pathologist. 

Side effects of a sentinel lymph node biopsy include pain, swelling, bleeding, bruising, scarring and infection. Uncommonly, patients may have an allergic reaction to the dye used for the procedure. Lymphoedema (see below) occurs uncommonly as a complication of sentinel lymph node biopsy. 

A positive sentinel lymph node biopsy means that cancer cells were detected in the removed lymph node(s). If this is the case, additional treatment options will be discussed with you. 

Lymph Node Dissection

In a lymph node dissection, also known as a lymphadenectomy, all the lymph nodes in a certain region of the body are surgically removed. This procedure may be performed for patients with melanoma that has spread to multiple lymph nodes in one region. 

Side effects of a lymph node dissection may include pain, bleeding, bruising, scarring and infection. After surgery, some patients experience an accumulation of fluid (known as a seroma) or blood in the area where the lymph nodes were removed, which may require another procedure to drain out the fluid or blood. Lymph node dissection can lead to lymphoedema as a long-term side effect. This is a condition where part of the body adjacent to the removed lymph nodes, such as an arm or leg, becomes chronically swollen from accumulation of lymphatic fluid caused by inadequate drainage.  

Skin Grafting

Skin grafting is a surgical procedure that involves transplanting healthy skin from one part of the body to cover a wound elsewhere. In some patients, skin grafting may be required after a wide local excision if a large area of skin was removed, leaving a surgical wound that is too large to heal otherwise. 

Targeted therapy

What is targeted therapy?

Targeted therapy refers to drug treatments that are designed to target specific structures in cancer cells. Typically, the targeted structures are molecules that cause the cancer cell to grow and divide. Blocking these molecules with drugs can therefore disrupt cell growth, leading to death of cancer cells. Importantly, the targeted molecules are unique to cancer cells. This aims to focus a drug’s actions on cancer cells while limiting adverse effects on normal, healthy cells. 

What types of targeted therapies used in melanoma? 

In melanoma, the main targeted therapies used are known as BRAF inhibitors and MEK inhibitors. BRAF and MEK inhibitors are tablets or capsules that are taken orally. In the treatment of melanoma, they are prescribed in combination with one another. The available combinations are: 

• Dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor), also referred to as Tafinlar and Mekinist 
• Encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor), also referred to as Braftovi and Mektovi 
• Vemurafenib (BRAF inhibitor) and cobimetinib (MEK inhibitor), also referred to as Zelboraf and Cotellic 

How does targeted therapy in melanoma work? 

BRAF and MEK are proteins found in normal cells which convey signals instructing the cell to grow and divide. When these growth signals function normally, cells grow and multiply in a controlled fashion. In melanoma, the BRAF gene, which provides the genetic information instructing a cell to produce the BRAF protein, is commonly mutated, resulting in the production of BRAF protein that behaves abnormally. The abnormal BRAF protein leads to overactive, uncontrolled growth signalling in the cell and excessive multiplication of cells, which contributes to the development of cancer. BRAF and MEK inhibitors work by binding to BRAF and MEK proteins and preventing them from transmitting their growth signals. 

Although BRAF is the primary target in melanoma, BRAF inhibitors and MEK inhibitors are used in combination with one another for enhanced anti-cancer effect (by blocking two signalling proteins simultaneously) and to prevent drug resistance from occurring. In addition, when used alone, BRAF inhibitors commonly cause severe side effects, particularly involving the skin, which is reduced by the addition of a MEK inhibitor. 

Am I eligible for targeted therapy? 

If your melanoma has a BRAF V600 mutation, you may be eligible for treatment with targeted therapy. Testing for the presence of a BRAF mutation testing is performed by analysing a sample of melanoma tumour, for example, from a biopsy or from previous surgery. Importantly, BRAF inhibitors are ineffective against melanoma without BRAF mutations. Additionally, BRAF inhibitors are only effective against a specific type of BRAF mutation, known as a BRAF V600 mutation. In brief, this terminology means that at codon 600 (indicating a certain position) of the BRAF gene, there is a mutation that changes the resulting BRAF protein to contain a different amino acid (the basic building block of a protein) instead of the correct amino acid, valine (V). 

For patients with BRAF V600 mutations, there are two main uses of BRAF and MEK inhibitors in melanoma: 

• As adjuvant therapy, i.e. treatment given after surgery to remove melanoma, given with the aim of reducing the chance of melanoma returning. 
• As treatment for unresectable/metastatic/stage IV melanoma. 

What are the side effects of targeted therapy? 

Although targeted therapies are designed to act specifically against cancer cells, side effects still occur. The most common side effects of BRAF and MEK inhibitors include fever, chills, fatigue, nausea, rash, diarrhoea and abnormal liver function (which can be measured on a blood test). 

Immunotherapy

What is immunotherapy? 

Immunotherapy refers to treatments that stimulate the body’s immune system to recognise and kill cancer cells. The immune system is the body’s defence system that protects it against unwanted intruders, such as infection and cancer. Under normal circumstances, the immune system is tightly regulated, maintaining a balance between eliminating unwanted, foreign organisms and cells, while recognising and avoiding causing harm to normal, healthy, “self” cells. Immunotherapy works by tipping this balance and stimulating the immune system towards a more attacking state.  

What types of immunotherapy are used in melanoma? 

The main immunotherapy drugs used in melanoma are: 

• Nivolumab 
• Ipilimumab 
• Pembrolizumab 
• Relatlimab

These drugs are given intravenously (by injection into a vein).

How does immunotherapy work in melanoma? 

The main immunotherapy drugs used in melanoma are classified as immune checkpoint inhibitors. Immune checkpoints are structures found on immune cells which transmit signals that reduce the strength of the immune cell’s response. These checkpoints are important for keeping the immune system in check. Otherwise, the immune system might become overactive and destroy normal, healthy cells, resulting in illness. 

Immune checkpoint inhibitors bind to immune checkpoints and block their signalling, causing activation of the immune system. An analogy commonly used to explain this is that immune checkpoints are like brakes for the immune system, and immune checkpoint inhibitors are like tools that release these brakes. 

The immune checkpoint inhibitors used for melanoma can be further classified into the following groups: 

• PD-1 inhibitors (nivolumab and pembrolizumab) 
• CTLA-4 inhibitors (ipilimumab) 
• LAG3 inhibitors (relatlimab) 

PD-1, CTLA-4 and LAG3 are simply names of different immune checkpoints. In other words, nivolumab is a drug that inhibits the PD-1 checkpoint. 

How is immunotherapy used in melanoma? 

Your treating team will discuss these options with you.

What are the side effects of immunotherapy? 

Immunotherapy treatment comes with the risk of a wide range of side effects. Most immunotherapy-related side effects occur because of overstimulation of the immune system, causing it to attack not only cancer cells, but also healthy human cells. 

The most common side effects of immunotherapy include: 

• Skin side effects, such as rash, itch and vitiligo (loss of skin pigmentation). 
• Endocrine side effects (i.e. side effects affecting hormone-producing organs), such as hypothyroidism (underactive thyroid), hyperthyroidism (overactive thyroid), hypopituitarism (underactive pituitary gland causing low levels of multiple important hormones) and adrenal insufficiency (underactive adrenal glands, causing low cortisol levels). 
• Musculoskeletal side effects, such as arthralgia (joint pain) and arthritis (inflammation of the joints).
• Gastrointestinal and liver side effects, such as colitis (inflammation of the bowels) and hepatitis (inflammation of the liver). 
• Respiratory side effects, such as pneumonitis (inflammation of the lungs). 
• Fatigue 

Examples of less common side effects include myocarditis (inflammation of the heart), nephritis (inflammation of the kidney), uveitis (inflammation of the uvea in the eye), pancreatitis (inflammation of the pancreas), myositis (inflammation of the heart), anaemia (low levels of red blood cells), diabetes (loss of insulin production by the pancreas) and encephalitis (inflammation of the brain). From this list, it probably seems as if immunotherapy can affect any part of the body. In fact, this is true to an extent, as the immune system can be stimulated to direct its activity towards any part of the body. 

Radiotherapy

Radiotherapy is also called radiation therapy.

Radiotherapy (also known as radiation therapy) is a type of treatment that uses high-energy radiation to damage the DNA of cancer cells, ultimately causing these cells to die or stop dividing. 

Patients with melanoma may be treated with radiotherapy for various reasons. 

• Radiotherapy is often used as a palliative treatment, meaning that the treatment is given with the aim of controlling symptoms, such as pain, rather than achieving cure or complete eradication of a cancer. 
• Radiotherapy is commonly used to treat brain metastases (melanoma tumours that have spread to the brain). 
• Less commonly, radiotherapy is given after surgery to reduce the risk of the melanoma relapsing, for example, after lymph node dissection where melanoma was detected in several removed lymph nodes. 
• In patients with metastatic melanoma, radiotherapy is sometimes used to control the growth of a metastasis (a secondary tumour that has formed from spread from the original melanoma), even it if is not causing symptoms. For example, a patient’s cancer may be well controlled by a particular drug treatment apart from one single metastasis that is growing. Radiotherapy can be a useful way of dealing with the single growing tumour while continuing the same drug treatment.

In the treatment of melanoma, radiotherapy is usually given as external beam radiotherapy, which means that the radiation is delivered from a source outside of the body. Before having treatment, you will first have a scan to determine the precise size and location of the tumour(s) being treated. This is used by a Radiation Oncologist to plan your treatment. During a radiotherapy treatment session, you lie still on a table, while a machine moves around you and directs radiation to the tumour(s) being treated. This process is like having a scan and does not cause any physical sensation as the radiation is being administered. In some cases, radiotherapy is given as a one-off treatment, while in other cases, treatment involves multiple treatment sessions over several days.

Side effects of radiotherapy include skin redness and pain, fatigue, nausea, diarrhoea and hair loss in the area being treated.