Answers to Top Questions About Stage 4 Melanoma

M.A., Health Writer
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Top Questions About Stage 4 Melanoma, Answered

If you're diagnosed with stage 4 melanoma that has spread beyond your regional lymph nodes, you no doubt have many questions. To answer some of the most important ones, meet melanoma expert John Kirkwood, M.D., of the University of Pittsburgh Department of Medicine. He is the Usher Professor of Medicine, Dermatology and Translational Science, director of the melanoma and skin cancer program, and is widely recognized for work in the areas of biological treatments and clinical trials.


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Q: Why is knowing what stage I have so important?

Treatment of cutaneous (skin) melanoma is guided by stage or disease localization, so accurate diagnosis of stage is critical. Staging principally determines the treatment used to manage melanoma. It's the foundation for basic assessment of the likelihood of cancer recurring after management by one of the current modalities. The Stages are: 0, 1A, 1B, 2A, 2B, 2C, 3A, 3B, 3C, 3D or 4. (Thanks to Valerie Guild, president of AIM at Melanoma, for this chart.)


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Q: I had a biopsy. Did you find any concerning features such as ulceration?

It's important that a biopsy obtain the entire tumor. Think of melanoma as an edifice on the skin, with millimeters of thickness like the stories of a building. Tumor thickness is determined at its thickest point, or Breslow thickness, and along with ulceration — skin breakdown on "top" of the tumor — may determine risk of progression. Ulceration can indicate rapid tumor growth. Research with staging groups found an ulcerated tumor behaves like a tumor with an "extra" millimeter of thickness.


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Q: What should I know about mitotic rate?

The American Joint Committee on Cancer (AJCC) eliminated mitotic rate (cell division) as one of the primary risk factors from current 2018 guidelines. You'd think that a tumor dividing more frequently creates higher risk. Mitotic rate was a modifier of the Stage TI category (<1.0 mm thickness) in the previous edition, but not currently. The AJCC Melanoma Expert Panel still strongly recommends assessing and recording mitotic rate for all primary melanomas at the original site.


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Q: If I need more tests, what do you recommend and when?

Not many other things are needed in terms of imaging studies, mapping, or biopsy if the melanoma thickness is <0.8. A melanoma of >0.8 mm thick is considered to be a primary tumor with a risk of lymph node spread that warrants further investigation. Risk of lymph node involvement approaches 10 percent when you get to 0.8 mm in the primary tumor thickness. Then, we recommend a sentinel lymph node mapping and a biopsy. This results in uncanny accuracy, more precise than even a CT or PET scan.


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Q: Tell me more

We inject a mapping blue dye, and more recently a tracer isotope into the skin, to image the sentinel lymph nodes, those to which the primary tumor drains. The technique then allows us to take a single gland out and look at it in detail — is it free of tumor or not? This helps us determine with greater clarity the destination or the lymph node group to which a melanoma might travel. It's one of the single most important staging tests we have.


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Q: How do you determine my prognosis?

Prognosis is defined by the stage of your tumor, according to the AJCC 8th edition 2018 guidelines. Staging includes microstaging of the primary melanoma and pathologic information about the regional lymph nodes after a sentinel lymph node biopsy. These factors determine appropriate medical management.


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Q: How would you decide on immunotherapies and targeted therapies?

There are two main categories of therapy: checkpoint blockade immunotherapy (CBI) and targeted therapy with BRAF/MEK inhibitors. If you have the BRAF mutation, as do almost 50 percent of patients, you can choose either one. If you don't have, CBI is your singular option. Your doctor will explain the risks including side effects, benefits, and alternatives.


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Q: What is Plan B if Plan A doesn't work?

If the first treatment uses CBI agents and it is ineffective or associated with intolerable toxicities, we'd consider options. New combinations of checkpoint blockade options are emerging, and such a clinical trial ought to be considered first. If you have the BRAF mutation, you can go to targeted therapies, a BRAF/MEK combination.


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More information about choosing a Plan B

If you've started on a BRAF/MEK combination, and still show disease progression, there are two options: Choose an immunotherapy with the first, second, or third generation CBI immunotherapies. Or go to other pairs of BRAF/MEK inhibitors. If you have difficulty tolerating one you can often tolerate a different one. They each have different toxicities and therapeutic efficacies.


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Q: Whichever treatment I choose, how can I manage my side effects?

Side effects of checkpoint blockade immunotherapy, used routinely in patients with or without BRAF mutations, have a very different spectrum of toxicity that we call autoimmune toxicity.

These side effects can involve a skin rash, colitis or gut inflammation, or inflammation of the liver. They can also target the endocrine glands, such as the thyroid or pituitary gland, resulting in gland dysfunction that can happen months into treatment last a long time.


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More about managing side effects

The BRAF and MEK inhibitors have a list of toxicities that include fatigue, gastrointestinal symptoms, skin eruptions, and fevers. These dissipate as treatment is either interrupted or dosage is reduced.


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And a final word about managing side effects

Side effects of targeted therapies end early and are managed by modifying dosage. As discussed, those from CBIs have much longer-lasting benefits, but also longer lasting toxicity. In addition to gland endocrinopathies as noted, colitis can last for months, and require aggressive treatment with steroids or immune-suppressive agents. Dermatitis may require steroids topically or systemically.