What are the treatments for melanoma ?
Cancer treatment is becoming increasingly personalized: for each patient, it will depend on the various elements collected during the diagnosis and pre-therapeutic assessment of the disease, including the characteristics of the cancer cells, their grade, the location, and the stage of the disease.
When melanoma is diagnosed, the primary care physician or the dermatologist who often made the diagnosis will refer the patient to a specialized cancer treatment center. The patient will be managed by a team of specialists to propose the most appropriate treatment options.
In practice, each patient's case will be discussed during a Multidisciplinary Team Meeting (MTM). This meeting includes at least a dermatologist, an oncologist, a radiotherapist, and a surgeon. A pathologist and/or a molecular biology specialist may also participate in this meeting.
Once a treatment plan has been chosen in the MTM, the doctor initially responsible for the patient will explain the treatment or, more precisely, the proposed therapeutic pathway in a special consultation known as the announcement consultation.
The term "therapeutic pathway" is indeed appropriate as a sometimes long and multi-step journey will be proposed to the patient.
During these steps, one or more of the five available cancer treatments will be used: two of these treatments are locoregional, surgery or radiotherapy.
The other three treatments are systemic (chemotherapy, targeted therapy, or immunotherapy). Chemotherapies and targeted therapies are administered orally or intravenously to reach cancer cells that may have spread.
Immunotherapies are administered intravenously to stimulate immune system cells to eliminate cancer cells. Some treatments, whether radiotherapy, chemotherapy, targeted therapy, or immunotherapy, may be performed alone or in combination before surgery. They are called neoadjuvant treatments. If they are prescribed after surgery, they are called adjuvant treatments.
The proposed treatment will primarily depend on the stage of the disease.
Treatment of early-stage melanomas
Surgery
For early-stage melanomas (stage 0, 1, or 2), the treatment is surgical: a wide excision with a margin of healthy tissue will be performed by the surgeon. The width of this margin of healthy tissue depends on the depth of the melanoma. For a melanoma less than 0.75 mm thick, the margin will be 1 cm. If the depth is greater, the margin will be at least 2 cm. Additionally, if the thickness is greater than 1 mm or if the tumor is 0.75 to 1 mm thick with ulceration, the excision of a particular lymph node, the sentinel lymph node, will be proposed.
💡 DID YOU KNOW ?
The sentinel lymph node is the first lymph node located near a melanoma. It is the first lymph node likely to be invaded by cancer cells in case of their spread.
To enable the surgeon to identify this lymph node, a dye or a mildly radioactive substance is injected into the tumor area. During the surgery, the surgeon can locate the sentinel lymph node by its blue coloration or by its radioactivity detected with a Geiger counter.
The surgeon will then remove this sentinel lymph node, and it will be examined under a microscope by a pathologist to determine if it is invaded by tumor cells.
After the surgical excision of a melanoma, a second surgical intervention may be necessary based on the results of the microscopic examination of the excised tissue. If the margins, which were assumed to be in healthy tissue at the time of the first surgery, are found to be invaded by tumor cells, this second intervention will be needed to widen the excision of the melanoma. If a large area of skin has been removed, reconstructive surgery may be performed. The surgeon takes a piece of skin, called a graft or skin flap, from another part of the body to reconstruct the area where the melanoma was located.
Immunotherapy
For early-stage melanomas, adjuvant immunotherapy may be proposed. This will be the case when the sentinel lymph node is invaded by cancer cells or in individuals with a high risk of cancer recurrence. The goal of immunotherapies is to stimulate the immune system to eliminate cancer cells. For the adjuvant treatment of early-stage melanomas with immunotherapy, a naturally occurring molecule in the body that stimulates the immune system, interferon alpha-2b, can be used. This molecule is administered at a high dose by injection several days a week for a year. Another immunotherapy can also be used. This is a checkpoint inhibitor that blocks the PD-1 checkpoint.
TO REMIND YOU
Immunotherapy treatments with checkpoint inhibitors have revolutionized the treatment of certain cancers, including melanomas. These treatments are based on three key discoveries :
- The first discover is the identification of checkpoint molecules : Checkpoints are specific molecules that can either accelerate or slow down the immune system's functioning.
- The second discover is cancer cells can exploit checkpoints that slow down the immune system to evade it. One such checkpoint is CTLA-4 , which is used to slow down the immune system. CTLA-4 is located on specific white blood cells, called helper T lymphocytes , which are essential for stimulating an immune response. CTLA-4 hinders the action of these lymphocytes. Another checkpoint is PD-L1 , present on the surface of cancer cells. This molecule binds to another molecule called PD-1 , found on cytotoxic T lymphocytes , the immune cells responsible for eliminating cancer cells. The binding of PD-L1 to PD-1 prevents cytotoxic T lymphocytes from performing their function and eliminating tumor cells.
- The third discover is drugs that block the CTLA-4, PD-1, or PD-L1 checkpoints can re-stimulate the immune system to eliminate tumor cells. These medications are a form of immunotherapy because, unlike chemotherapy which directly kills cancer cells, they stimulate the immune system to destroy cancer cells. These immunotherapies are often more effective if the cancer cells have numerous PD-L1 molecules on their surface.These drugs used in immunotherapy are artificially produced monoclonal antibodies administered intravenously . Like natural antibodies that recognize a specific target, the monoclonal antibodies used in cancer immunotherapy are designed to recognize one of the checkpoints: CTLA-4, PD-1, or PD-L1.
Treatment of stage 3 melanomas
Surgery
For locally advanced melanoma, which includes all stage 3 melanomas, the cancer has spread to nearby lymph nodes. The treatment for these melanomas begins with surgical excision, including the removal of affected lymph nodes (complete lymph node dissection).
Targeted therapies
An adjuvant treatment will be offered to all patients in good general health. This treatment will depend on the mutations identified in the tumor cell DNA. Over half of melanomas have a particular mutation, the V600E mutation, in the BRAF gene.
💡 DID YOU KNOW ?
Within cells, there are proteins that function in a cascade, acting one after another to influence cell behavior. These proteins form an intracellular pathway, such as the RAS, RAF, MEK, ERK proteins. This pathway plays a crucial role in cell proliferation and survival. The BRAF gene is responsible for producing one of these proteins, the BRAF protein . A mutation in the BRAF gene, specifically the V600E mutation, is responsible of the production of a mutated protein. By blocking the mutated protein, it is possible to halt cell proliferation.
For patients with the V600E mutation in the BRAF gene, there are medications that specifically block the mutated BRAF protein to prevent tumor cell multiplication. These anti-BRAF medications are used as adjuvant treatments in combination with another drug that blocks the MEK protein, which is also involved in tumor cell proliferation. These anti-BRAF or anti-MEK medications are known as targeted therapies.
TO REMIND YOU
As their name suggests, targeted therapies are directed against specific targets involved in the transformation of normal cells into cancerous cells, the development of malignant tumors, or the proliferation of cancer cells.
These targets can be located on the surface or inside cancer cells. On the surface, they can be specific receptors like the Epidermal Growth Factor Receptor (EGFR). Internally, they can be molecules like RAS, RAF, MEK, or ERK, which are part of intracellular pathways crucial for cancer cell multiplication. By blocking these targets with a targeted therapy, tumor growth is directly inhibited.
Targeted therapies include monoclonal antibodies , which are large molecules that target extracellular targets and are administered intravenously , and small molecules that target intracellular targets and are taken orally . There are currently around fifty different targeted therapies available.
Immunotherapy
For patients with the V600E mutation in the BRAF gene, an adjuvant treatment with an immunotherapy targeting the CTLA-4 checkpoint or the PD-1 checkpoint may also be proposed.
For patients without the BRAF gene mutation, an adjuvant treatment with an immunotherapy targeting the PD-1 checkpoint will be offered.
Treatment of metastatic melanomas
For metastatic melanoma (stage 4), surgery has a limited role. However, it can be considered in certain situations such as a single metastasis. The excision of a few metastases may also be performed after treatment with immunotherapy or targeted therapy.
The first proposed treatment, known as "first-line treatment", will depend on the presence or absence of the V600E mutation in the BRAF gene in the tumor cells.
Treatment for BRAF gene mutation
For patients with a BRAF mutation, the usual treatment is a combination of an anti-BRAF medication with an anti-MEK medication. Another option is an immunotherapy targeting the PD-1 checkpoint. If this first-line treatment fails, a second treatment, known as "second-line treatment", will be offered. The usual second-line treatment is an immunotherapy targeting the PD-1 checkpoint.
If the first-line treatment was already an immunotherapy targeting the PD-1 checkpoint, a combination of an anti-BRAF medication with an anti-MEK medication will then be offered as second-line treatment. If this second-line treatment fails, a new treatment, known as "third-line treatment", will be proposed. This will be an immunotherapy targeting the CTLA-4 checkpoint or chemotherapy with an antineoplastic agent.
Treatment for absence of BRAF gene mutation
For patients whose tumor cells do not have a BRAF mutation, the usual first-line treatment is an immunotherapy targeting the PD-1 checkpoint. If the patient's general condition is good, a combination treatment with an immunotherapy targeting the PD-1 checkpoint and an immunotherapy targeting the CTLA-4 checkpoint will be proposed. For second-line treatment, an immunotherapy targeting the CTLA-4 checkpoint is recommended. For third-line treatment, chemotherapy with an antineoplastic agent may be proposed.
Finally, melanoma is one of the cancers that has most benefited from advances in scientific and clinical research over the past fifteen years. Scientific research has enabled the identification of immune system checkpoints and the various mechanisms used by cancer cells to proliferate.
Clinical research, through clinical trials, has led to the development of checkpoint immunotherapies and targeted therapies directed against molecules involved in the multiplication of cancer cells. These clinical trials lead to permanent changes in the management of patients with melanoma, whether they are at an early stage or a metastatic stage. Today, patients with melanoma can benefit from immunotherapy or targeted therapy when one or the other of these treatments is necessary. Among the very recent advances from clinical trials, immunotherapy is now being offered to some patients before surgical intervention. There is no doubt that the current clinical trials will lead to further progress.
--
Article updated on Nov 19, 2024
Get a second opinion for your cancer from an expert
Response within 7 days