MELANOMA CASE 1 Flashcards
PH INITIATIVES AGAINST MELANOMA IN AUSTRALIA HAVE RAN SINCE?
1970s
COUNTRY WITH HIGHEST MELANOMA RISK?
AUSTRALIA
WHY CAN IT BE CHALLENGING TO EFFECTIVELY COMMUNICATE WHAT A HEALTHY AMOUNT OF SUN EXPOSURE IS?
Communicating the risks and benefits of sunlight exposure is a challenge. Exposure to the sun can boost vitamin D levels, but too much time spent in the sun increases the risk of skin cancer. There are a number of at risk-groups, those who are vitamin D deficient and also those at risk of increased UV exposure, getting the balance right will be key for reducing the incidence of melanoma and vitamin D deficiency and associated disorders.
Groups of people who should take extra care to avoid skin damage and skin cancer:
children (particularly babies) and young people
people who tend to burn rather than tan
people with lighter skin, fair or red hair, blue or green eyes, or who have lots of freckles
people with many moles
people who are immunosuppressed (that is, they have less resistance to skin problems as a result of a disease or use of particular drugs)
people with a personal or family history of skin cancer (even if their natural skin colour is darker than that of the family member who had cancer).
Groups who spend a lot of time in the sun and so are at increased risk of skin cancer, such as:
outdoor workers
those with outdoor hobbies, for example, sailing or golf.
Groups with high, but intermittent, exposure to sunlight and who are therefore at increased risk of skin cancer. This includes people who sunbathe or take holidays in sunny countries.
Groups who have little or no exposure to the sun for cultural reasons or because they are housebound or otherwise confined indoors for long periods. For example, people who are frail or in institutions, or people who work indoors all day. These people are at increased risk of low vitamin D status.
% OF MELANOMA CASES WITH BRAF MUTATION?
CCA 40%
BRAF MUTATION AND MELANOMA?
- BRAF gene activates the mitogen-activated protein (MAPK) pathway
- The Mitogen Activated Protein Kinase (MAPK) pathway plays a key role in melanoma development making it an important therapeutic target. In normal cells, the tightly regulated pathway relays extracellular signals from cell membrane to nucleus via a cascade of phosphorylation events (involved in cellular proliferation, differentiation, development, inflammatory responses and apoptosis in mammalian cells)
- mutations in the BRAF gene can be inherited from parents, however this is rare, most mutations occur later in life
HOW CAN PERFORMING GENETIC TESTS ON TUMOR BIOPSY FOR MELANOMA INFORM THERAPY OPTIONS?
If there is a BRAF mutation, combining a BRAF inhibitor with a MEK inhibitor, which also targets the MAPK pathway, has been shown to improve the outcome of patients with metastatic melanoma as well as reduce the risk of recurrence when used as adjuvant therapy in patients with resected stage 3 melanoma
Dabrafenib and trametinib ?
- Both drugs are targeted therapy drugs known as cancer growth inhibitors.
- Taken orally
- Only used if there is BRAF mutation (they block BRAF)
Dabrafenib and trametinib may be used to treat melanoma that:
- is stage 3 and was completely removed with surgery – you have the drugs for up to 1 year to try to reduce the risk of the melanoma coming back (called adjuvant treatment)
- cannot be removed with surgery or melanoma that has spread to other organs of the body
(may also be used to treat advanced non-small cell lung cancer (NSCLC))
NIVOLUMAB?
- TYPE OF CHECKPOINT INHIBITOR
- GIVEN INTRAVENOUSLY
Nivolumab is a monoclonal antibody that binds to the PD-1 protein on the surface of T cells blocking the interaction with PD-L1, a ligand on the surface on tumour cells. The interaction of PD-1 with PD-L1 inhibits the function of T cells preventing them from attacking tumour cells. By blocking this interaction, Nivolumab unleashes the cytotoxic activity of T cells resulting in the destruction of tumour cells.
IPILIMUMAB?
- TYPE OF CHECKPOINT INHIBITOR
- GIVEN INTRAVENOUSLY
Ipilimumab is a monoclonal antibody that binds CTLA-4 on the surface of T cells blocking the interaction with proteins (CD80 and CD86) on the surface of antigen-presenting cells. The interaction of CTLA-4 with CD80 and CD86 inhibit T cell activation and this is reversed when this interaction is blocked by Ipilimumab.
MOST COMMON SITES OF MELANOMA METASTASIS?
Common sites for melanoma metastasis includes: skin, lung, brain, liver, bone, and, intestine
MELANOMA ABCDE RULE
Asymmetry Border irregularity Colour variability/Change Different Evolving
Asymmetry
A melanocytic naevus (harmless mole) is usually symmetrical, whereas melanoma is often irregular or asymmetrical in shape and/or colour.
Border irregularity
A melanocytic naevus has smooth, even borders, whereas a melanoma often has irregular, blurry, or jagged edges and hard-to-define border.
On careful inspection, the pigmented component of a flat melanocytic naevus fades out towards the edge, whereas the edges of a solar lentigo or a seborrhoeic keratosis are well defined. The edges of a melanoma tend to have both well-defined and fading segments.
B can also used for ‘black’, which is an uncommon colour for a melanocytic naevus in a white-skinned individual, but may be typical in skin of colour. The colour black however can occur in seborrhoeic keratoses in all skin types and ink spot lentigo in fair skin.
Colour variability and Changing colour
A melanocytic naevus usually has a single shade of colour or two colours with one occurring inside the other or regularly repeated (generally pink, brown, or tan).
Melanoma can be brown (96%) but can have as many as five or six colours such as blue, black, tan, grey, pink, and red: 50% of melanomas include these uncommon colours. These colours are unevenly or irregularly distributed. C is also for Changing Colour.
Different
Most people have a ‘signature naevus’ - all their melanocytic naevi resemble each other. A melanoma appears unique and very different from the patient’s other lesions.
A pigmented lesion that is obviously different from the others is sometimes called an ‘ugly duckling’, ‘black sheep’, ‘lone ranger’, or ‘odd-mole-out’ and must be considered suspicious even if it does not fulfil the ABCDEFG criteria.
Evolving
A melanocytic naevus is usually stable and does not change in size, shape, or colour, whereas a melanoma changes over time. Change in size, colour, shape, or structure may be noted over months to years. However melanoma accounts for less than 3% of all changing skin lesions.
Treatment of Melanoma Skin Cancer, by Stage
Treating stage 0 melanoma
Stage 0 melanoma (melanoma in situ) has not grown deeper than the top layer of the skin (the epidermis). It is usually treated by surgery (wide excision) to remove the melanoma and a small margin of normal skin around it. The removed sample is then sent to a lab to be looked at with a microscope. If cancer cells are seen at the edges of the sample, a second, wider excision of the area may be done.
Some doctors may consider the use of imiquimod cream (Zyclara) or radiation therapy instead of surgery, although not all doctors agree with this.
For melanomas in sensitive areas on the face, some doctors may use Mohs surgery or even imiquimod cream if surgery might be disfiguring, although not all doctors agree with these uses.
Treating stage I melanoma
Stage I melanoma is typically treated by wide excision (surgery to remove the melanoma as well as a margin of normal skin around it). The width of the margin depends on the thickness and location of the melanoma. Most often, no other treatment is needed.
Some doctors may recommend a sentinel lymph node biopsy (SLNB) to look for cancer in nearby lymph nodes, especially if the melanoma is stage IB or has other characteristics that make it more likely to have spread. You and your doctor should discuss this option.
If the SLNB does not find cancer cells in the lymph nodes, then no further treatment is needed, although close follow-up is still important.
If cancer cells are found on the SLNB, a lymph node dissection (removal of all lymph nodes near the cancer) might be recommended. Another option might be to watch the lymph nodes closely by getting an ultrasound of the nodes every few months.
If the SLNB found cancer, adjuvant (additional) treatment with an immune checkpoint inhibitor or targeted therapy drugs (if the melanoma has a BRAF gene mutation) might be recommended to try to lower the chance the melanoma will come back. Other drugs or perhaps vaccines might also be options as part of a clinical trial.
Treating stage II melanoma Wide excision (surgery to remove the melanoma and a margin of normal skin around it) is the standard treatment for stage II melanoma. The width of the margin depends on the thickness and location of the melanoma.
Because the melanoma may have spread to nearby lymph nodes, many doctors recommend a sentinel lymph node biopsy (SLNB) as well. This is an option that you and your doctor should discuss.
If a SLNB is done and does not find cancer cells in the lymph nodes, then sometimes no further treatment is needed, but close follow-up is still important. Other times, for certain Stage II melanomas, the immune checkpoint inhibitor pembrolizumab might be given after surgery to reduce the risk of the cancer returning.
If the SLNB finds that the sentinel node contains cancer cells (which changes the cancer stage to stage III – see below), then a lymph node dissection (where all the lymph nodes in that area are surgically removed) might be done right away. Adjuvant (additional) treatment with an immune checkpoint inhibitor or targeted therapy drugs (if the melanoma has a BRAF gene mutation) might be recommended to try to lower the chance the melanoma will come back. Other drugs or perhaps vaccines might also be options as well as part of a clinical trial. In other cases where the SLNB finds cancer, the lymph nodes might be watched closely with an ultrasound of the nodes every few months, instead of doing a lymph node dissection right then. Your doctor will discuss the best options with you depending on the details of your situation.
Treating stage III melanoma
These cancers have already reached the lymph nodes when the melanoma is first diagnosed. Surgical treatment for stage III melanoma usually requires wide excision of the primary tumor as in earlier stages, along with lymph node dissection.
After surgery, (additional) adjuvant treatment with an immune checkpoint inhibitor or with targeted therapy drugs (for cancers with BRAF gene changes) may help lower the risk of the melanoma coming back. Other drugs or perhaps vaccines may also be recommended as part of a clinical trial to try to reduce the chance the melanoma will come back. Another option is to give radiation therapy to the areas where the lymph nodes were removed, especially if many of the nodes contain cancer.
If melanoma tumors are found in nearby lymph vessels in or just under the skin (known as in-transit tumors), they should all be removed, if possible. Other options include injections of the T-VEC vaccine (Imlygic), Bacille Calmette-Guerin (BCG) vaccine, or interleukin-2 (IL-2) directly into the melanoma; radiation therapy; or applying imiquimod cream. For melanomas on an arm or leg, another option might be isolated limb perfusion or isolated limb infusion (infusing just the limb with chemotherapy). Other possible treatments might include targeted therapy (for melanomas with a BRAF or C-KIT gene change), immunotherapy, or chemotherapy.
Some people with stage III melanoma might not be cured with current treatments, so they may want to think about taking part in a clinical trial of newer treatments.
Treating stage IV melanoma
Stage IV melanomas have already spread (metastasized) to distant lymph nodes or other areas of the body. Skin tumors or enlarged lymph nodes causing symptoms can often be removed by surgery or treated with radiation therapy.
Metastases in internal organs are sometimes removed, depending on how many there are, where they are, and how likely they are to cause symptoms. Metastases that cause symptoms but cannot be removed may be treated with radiation, immunotherapy, targeted therapy, or chemotherapy.
The treatment of widespread melanomas has changed in recent years as newer forms of immunotherapy and targeted drugs have been shown to be more effective than chemotherapy.
Immunotherapy drugs called checkpoint inhibitors such as pembrolizumab (Keytruda) or nivolumab (Opdivo) are typically the first drugs tried, especially in people whose cancer cells do not have BRAF gene changes. These drugs can shrink tumors for long periods of time in some people. Ipilimumab (Yervoy), a different type of checkpoint inhibitor, is not typically used by itself as the first treatment, although it might be combined with nivolumab or pembrolizumab. This slightly increase the chances that the tumor(s) will shrink, although it’s also more likely to result in serious side effects, which needs to be considered carefully. People who get any of these drugs need to be watched closely for serious side effects..
In about half of all melanomas, the cancer cells have changes in the BRAF gene. If this gene change is found, treatment with newer targeted therapy drugs – typically a combination of a BRAF inhibitor and a MEK inhibitor – might be a good option. Immune checkpoint inhibitors such as pembrolizumab or nivolumab are another option for these people. Doctors aren’t sure if targeted therapy or immunotherapy is better as the first treatment. This is now being studied. But there might be situations where it makes sense to use one instead of the other. For example, the targeted drugs are more likely to shrink tumors quickly, so they might be preferred in cases where this is important. In either case, if one type of treatment isn’t working, the other can be tried.
A small portion of melanomas have changes in the C-KIT gene. These melanomas might be helped by targeted drugs such as imatinib (Gleevec) and nilotinib (Tasigna), although these drugs often stop working eventually.
Immunotherapy using interleukin-2 (IL-2) can help a small number of people with stage IV melanoma live longer, and it might be tried if immune checkpoint inhibitors aren’t working. Higher doses of IL-2 seem to be more effective, but they can also have more severe side effects, so it might need to be given in the hospital.
Chemotherapy can help some people with stage IV melanoma, but other treatments are usually tried first. Dacarbazine (DTIC) and temozolomide (Temodar) are the chemo drugs used most often, either by themselves or combined with other drugs. Even when chemotherapy shrinks these cancers, the cancer usually starts growing again within several months.
It’s important to carefully consider the possible benefits and side effects of any recommended treatment before starting it.
Because stage IV melanoma is often hard to cure with current treatments, patients may want to think about taking part in a clinical trial. Many studies are now looking at new targeted drugs, immunotherapies, chemotherapy drugs, and combinations of different types of treatments. (See What’s New in Melanoma Skin Cancer Research?)
Treating recurrent melanoma
Treatment of melanoma that comes back after initial treatment depends on the stage of the original melanoma, what treatments a person has already had, where the melanoma comes back, and other factors.
Local recurrence
Melanoma might come back in the skin near the site of the original tumor, sometimes even in the scar from the surgery. In general, these local (skin) recurrences are treated with surgery similar to what would be recommended for a primary melanoma. This might include a sentinel lymph node biopsy (SLNB). Depending on the results of the SLNB, other treatments might be recommended as well.
In-transit recurrence
If melanoma recurs in nearby lymph vessels in or just under the skin (known as in-transit recurrence), it should be removed, if possible. Other options include injections of the T-VEC vaccine (Imlygic), Bacille Calmette-Guerin (BCG) vaccine, or interleukin-2 (IL-2) directly into the melanoma; radiation therapy; or applying imiquimod cream. For melanomas on an arm or leg, another option might be isolated limb perfusion or isolated limb infusion (infusing just the limb with chemotherapy). Other possible treatments might include targeted therapy (for melanomas with a BRAF or C-KIT gene change), immunotherapy, or chemotherapy.
Recurrence in nearby lymph nodes
If nearby lymph nodes weren’t all removed during the initial treatment, the melanoma might come back in these lymph nodes. Lymph node recurrence is treated by lymph node dissection if it can be done, sometimes followed by adjuvant (additional) treatments such as radiation therapy and/or immunotherapy or targeted therapy (for cancers with BRAF gene changes). If surgery is not an option, radiation therapy or systemic treatment (immunotherapy, targeted therapy, or chemo) can be used.
Recurrence in other parts of the body
Melanoma can also come back in distant parts of the body. Almost any organ can be affected. Most often, the melanoma will come back in the lungs, bones, liver, or brain. Treatment for these recurrences is generally the same as for stage IV melanoma (see above). Melanomas that recur on an arm or leg may be treated with isolated limb perfusion/infusion chemotherapy.
Melanoma that comes back in the brain can be hard to treat. Single tumors can sometimes be removed by surgery. Radiation therapy to the brain (stereotactic radiosurgery or whole brain radiation therapy) may help as well. Systemic treatments (immunotherapy, targeted therapy, or chemo) might also be tried.
As with other stages of melanoma, people with recurrent melanoma may want to think about taking part in a clinical trial.
DECENTRALISED CLINICAL TRIAL
In decentralized clinical trials, patient visits for healthcare provider interaction and laboratory tests are localized in the patient’s community. Medications for the study are provided either directly to the patient or the local healthcare facility.
- PATIENTS PARTICIPATING AS MUCH AS POSSIBLE FROM HOME/CLOSE TO HOME
SYSTEMIC VS LOCAL CANCER THERAPY
Treatment that affects your entire body. This is called systemic therapy. This includes chemotherapy, targeted therapy, hormone therapy and immunotherapy.
Treatment for the area with cancer. This is called local therapy. This includes surgery, radiation therapy ext
