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Treatment of Melanoma

Treatment of melanoma is determined by the stage. For advanced (metastatic) melanoma, treatment is not “one size fits all” but will be personalised with the guidance of your treating clinician.

Treatment Options – Early Stage Melanoma

Surgery for a primary melanoma –Stages 0-I-II

For patients in stage 0, I or II, surgery of a primary melanoma includes, but may not be limited to, the removal of the primary tumour with a margin of normal skin.

Excision margins involve the removal of normal skin and flesh from around the primary tumour with the aim of ensuring any residual cancer cells have been removed. The margin of skin and fat relates to the thickness of the tumour. For a Level 1, in situ melanoma the margin should be 0.5–1.0cm. For stage I–II melanoma the margin should be between 1-2cm. Sentinel lymph node biopsy is considered in patients with Stage Ib – IIc primary melanoma.

A skin graft or a skin flap may be required after the removal of the melanoma. After the surgery, a pathologist determines whether margins are clear by examining the entire specimen and the excised tumour edges.

Treatment Options – Advanced Melanoma

Surgery to remove lymph nodes

For patients with stage III, surgery is also the main treatment undertaken. The most common site for the lymph nodes to be removed is in the regions: neck; arm pit (axilla) and groin. A removal or block dissection of lymph nodes in the region surrounding the node/s that tested positive for melanoma is undertaken because there is a risk that there may be other nodes involved with melanoma that cannot be seen or felt. The pathologist helps to determine that the surgical margins are clear of the disease and the number of lymph nodes involved.

Adjuvant Systemic Therapy

When drugs are given to treat the whole person, it is called systemic therapy. These treatments work with the aim to treat the whole body and remove any cancer cells that may have escaped into the body. It is this disease that has the risk that it may appear as a recurrence of melanoma.  Treatment after surgery is called adjuvant therapy. The drugs can be in the form of oral therapy that targets a protein the melanoma expresses or immunotherapy, which is therapy that is designed to make your body’s immune system recognise any residual cancer cell and act against them. Adjuvant therapy is designed to try and prevent melanoma recurrence and improve the survival beyond what surgery alone can offer. The availability of these therapies and whether they are right for you, will be discussed with you by your treating team.


Immunotherapy

Immunotherapy treatments work by stimulating a patient’s own immune system so that it can recognise and destroy cancer cells more effectively. These therapies modulate various components of the immune system.

Keytruda (pembrolizumab)

Keytruda is an immunotherapy which works with the body’s immune system to treat cancer.  Keytruda works by blocking a pathway that allows tumours to remain hidden from the immune system This helps to increase the ability of the body’s immune system to detect and fight tumor cells. Keytruda is also known as a checkpoint inhibitor.

Checkpoint inhibitors like Keytruda work by blocking the interaction between PD-L1 (a protein found on the surface of tumor cells) with PD-1 ( a receptor found on immune cells). Blocking the PD-1/PD-L1 connection allows a patient’s immune system to recognize and kill cancer cells.

Keytruda targets PD-1 and it works by “disarming” the tumour’s defences that block the the ability of T cells (white blood cells critical for the body’s immune responses) to attack the tumour.

Keytruda is administered intravenously every 3 or 6 weeks.

Keytruda is generally well tolerated but common side effects include fatigue and joint pain. Inflammation of major organs including intestines, lungs and liver can also occur.  It is important that patients tell their healthcare professionals about any side effects, even if they seem minor as inflammation may cause serious damage to your body and some inflammatory conditions may be life-threatening.

Keytruda is listed on the  Pharmaceutical Benefits Scheme (PBS) for first line treatment of unresectable Stage III or IV melanoma regardless of BRAF mutation.
As of the 01 September 2020, Keytruda has been listed on the PBS as an adjuvant therapy for resected Stage III melanoma patients.

Opdivo® (nivolumab or “nivo”)

Opdivo is an immunotherapy which works with the body’s immune system to treat cancer.  Opdivo works by blocking a pathway that allows tumours to remain hidden from the immune system This helps to increase the ability of the body’s immune system to detect and fight tumor cells. Opdivo is also known as a checkpoint inhibitor.

Checkpoint inhibitors like Opdivo work by blocking the interaction between PD-L1 (a protein found on the surface of tumor cells) with PD-1 ( a receptor found on immune cells). Blocking the PD-1/PD-L1 connection allows a patient’s immune system to recognize and kill cancer cells.

Opdivo targets PD-1 and it works by “disarming” the tumour’s defences that block the the ability of T cells (white blood cells critical for the body’s immune responses) to attack the tumour.

Opdivo is administered intravenously every 2 or 4 weeks.

Opdivo is generally well tolerated but common side effects include fatigue and joint pain. Inflammation of major organs including intestines, lungs and liver can also occur.  It is important that patients tell their healthcare professionals about any side effects, even if they seem minor as inflammation may cause serious damage to your body and some inflammatory conditions may be life-threatening.

Opdivo is listed on the  Pharmaceutical Benefits Scheme (PBS) for all resected Stage III patients, regardless of BRAF mutation.

Yervoy® (ipilimumab or “ipi”)

Yervoy is an immunotherapy which works with the body’s immune system to treat cancer.  It is also known as a checkpoint inhibitor.

Yervoy is an antibody that targets CTLA-4 expressed on T-cells. CTLA-4 acts like a “brake” on the immune system.  By binding to CTLA-4, Yervoy releases the brake which allows the immune system to build its T-cell army to respond to cancer. T cells are white blood cells critical for the body’s immune responses.

Sometimes, in this process, the T-cells may cause inflammation of healthy cells and may result in serious side effects.  Side effects are generally manageable, if appropriately identified and treated.

Healthcare professionals use established guidelines to treat these side effects and the earlier the side effect is identified and treated, the better.  It is important that patients tell their healthcare professionals about any side effects, even if they seem minor, as inflammation may cause serious damage to your body and some inflammatory conditions may be life-threatening.

Common sites of inflammation include the skin (itchiness and rashes), the liver (causing liver enzymes to increase) and the bowel and stomach (causing diarrhoea).

Yervoy treatment consists of four infusions administered every 3 weeks (ie over 10 weeks) through an intravenous infusion (ie a drip).

Yervoy is listed on the Pharmaceutical Benefits Scheme (PBS) for advanced melanoma and may be given in combination with one of the other immunotherapies.

Combination Treatment – Yervoy (ipilumimab) and Opdivo (nivolumab)

Opdivo and Yervoy target different checkpoint pathways (PD-1 and CTLA-4) to boost the immune system’s response to cancer.

When used together, they have a complementary effect.  In summary, Yervoy builds the T-cell army and Opdivo unleashes the T-cell army against the tumour.

Sometimes, in this process, the T-cells may cause inflammation of healthy cells and may result in serious side effects.  (See Yervoy and Opdivo side effects.)  More people experience serious side effects when treated with the combination of Opdivo and Yervoy than single agent treatment.   Side effects are generally manageable, if appropriately identified and treated. Healthcare professionals use established guidelines to treat these side effects and the earlier the side effect is identified and treated, the better.  It is important that patients tell their healthcare professionals about any side effects, even if they seem minor, as inflammation may cause serious damage to your body and some inflammatory conditions may be life-threatening.

When used in combination:

  • Opdivo and Yervoy are administered together for the first four treatments, every 3 weeks (ie four treatments over 10 weeks)
  • Opdivo is then administered on its own every 2 or 4 weeks
  • Treatment is stopped if the cancer progresses or there are unacceptable side effects.

The combination Yervoy and Opdivo is listed on the Pharmaceutical Benefits Scheme (PBS) as a first-line treatment for melanoma patients with advanced disease who are BRAF positive.

Imlygic (Talimogene Laherparepvec or Tvec)

Imlygic is a genetically modified live oncolytic herpes virus designed to replicate within cancer cells and produce an immunostimulatory protein called GM-CSF (granulocyte-macrophage colony-stimulating factor).

Imlygic is injected directly into the melanoma tumour, causing cell lysis, or death, which ruptures the tumors, and releases tumor-derived antigens, which along with GM-CSF, may promote an anti-tumor immune response. However, the exact mechanism of action is unknown.

Imlygic is a live virus in patients and due to difficulties with importation, storing and administration it is not available in Australia.

 


Targeted Therapies

Melanoma is one of the cancers with the highest frequency of genetic mutations. There are several genetic mutation tests available and identifying if your tumour has a mutation can be important in determining your treatment pathway.  The genetic tests are performed on a tumour sample from a biopsy.

Mutations can result in abnormal signalling (in the MAPK pathway) which can stimulate the growth of melanoma cells. Mutated signalling pathways in melanoma cells are targets for therapy. If no mutation is found the tumour is referred to as “wild type”, meaning no specific gene mutation has been identified in the melanoma tumour.

BRAF is a protein found in the cells of your body. It is important for normal cell growth. BRAF is turned on by a special chemical signal. In your melanoma, the BRAF protein has a mutation which means it is ‘on’ all the time. This results in abnormal cell growth and may have led to the development of your melanoma. The BRAF mutation is found in approximately half of all melanomas and is the most common genetic mutation associated with melanoma.

NRAS is the second most common mutation found in advanced melanoma found in 10-12% of melanomas. These tumours tend to be thicker and grow faster.

c-KIT mutations are most commonly found in Asian populations. They are also more likely to be found in melanomas that start on the palms of the hands, soles of the feet, under nails, inside the mouth and nose, or other mucosal areas.

Approximately 40-45% of melanomas have BRAFV600 mutations. In these patients targeted therapies (oral therapies that turn the BRAF mutation off) can be used to block uncontrolled signals and slow down the rate of tumour growth.

 

Tafinlar (dabrafenib) and Mekinist (trametinib)

Tafinlar and Mekinist are treatments used in combination for those with the BRAFV600 mutation.
They are both protein inhibitors and target the pathways that allow tumour growth, slowing down cell growth and division.

Tafinlar and Mekinist used in combination form a double blockade and the combination of the two inhibitors (BRAF inhibitor and MEK inhibitor) has shown significantly improved survival and delayed drug resistance over the use of a single agent.

This treatment combination is taken orally (in pill form) each day.

Tafinlar and Mekinist can cause side effects. The most common side effects include fever, fatigue, diarrhoea, nausea, vomiting, skin rash, swelling of ankles or feet and eye problems.

The combination of Tafinlar and Mekinist is listed on the Pharmaceutical Benefits Scheme (PBS) for the treatment of BRAFV600 mutation-positive unresectable metastatic melanoma. It has also now been made available as an adjuvant therapy following regional lymph node surgery for patients with Stage IIIB, IIIC and IIID melanoma.

Zelboraf (vemurafenib) and Cotellic (cobimetinib)

Zelboraf and Cotellic are treatments used in combination for those with the BRAFV600 mutation.
They are both protein inhibitors and target the pathways that allow tumour growth, slowing down cell growth and division.

Zelboraf and Cotellic used in combination form a double blockade and the combination of the two inhibitors (BRAF inhibitor and MEK inhibitor) has shown significantly improved survival and delayed drug resistance over the use of a single agent.

This treatment combination is taken orally (in pill form) each day.

Zelboraf and Cotellic can cause side effects. The most common side effects include sunburn or sun sensitivity, Cutaneous Squamous Cell Carcinoma (lesions) skin rash, blistering, swelling of the face, hands, or soles of the feet, joint discomfort and eye problems.

The combination of Zelboraf and Cotellic is listed on the Pharmaceutical Benefits Scheme (PBS) for the treatment of BRAFV600 mutation-positive unresectable metastatic melanoma.


Radiotherapy

Radiation therapy is a localised treatment that uses high energy radiation to kill cancer cells. It does this by damaging the DNA of cells that are dividing. Radiotherapy is commonly used to relieve symptoms from metastases (secondary cancer that has spread from the first or primary site) from sites such as the brain, bones or lungs. Radiotherapy may be used as an alternative to surgery in patients who are medically unfit for surgery or who cannot have the melanoma removed surgically because it is too extensive. For stage III melanoma post-operative radiotherapy may be considered in patients who are considered to be in a high risk group for the melanoma recurring in the operated region.

For those with brain metastases whole brain radiation or Stereotactic radiosurgery (SRS) may be used. SRS involves several powerful beams of radiation located at different angles around the head come together to focus precisely on the tumor. Gamma Knife is one of the most advanced forms of SRS.


Chemotherapy

Chemotherapy is a systemic treatment, it focuses on killing cancer cells by targeting rapidly dividing cells. Unfortunately cancer cells are not the only rapidly dividing cells; the digestive system cells, hair cells and other healthy cells are also rapidly dividing cells. It is the damage to healthy cells that cause the side effects from chemotherapy. Common side effects include hair loss, nausea, fatigue and effects on the bone marrow which normally has a high turnover of cells compared with the rest of the body.

Chemotherapy is rarely used in Australia because of its limited efficacy in melanoma.

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