Rare Classroom: Metastatic Melanoma

Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Metastatic Melanoma

Sometimes called malignant melanoma.

What is Metastatic Melanoma?

  • Melanoma is the most dangerous form of skin cancer​
  • It develops when unrepaired DNA damage to skin cells triggers mutations that lead the skin cells to multiply rapidly and form malignant tumors​
  • The tumors develop in melanocytes in the basal layer of the epidermis​
  • Melanoma generally starts as a single tumor or lesion​
  • Most melanomas arise in the skin but can also begin in mucous membranes, the eye, and occasionally internal organs​
  • If melanoma is recognized and treated early, it is almost always curable​
  • Metastatic melanoma is a melanoma that has spread beyond the original site to the lymph nodes or distant organs​
  • Metastatic melanoma is also known as:​
    • Advanced melanoma​
    • Stage IV melanoma​

How Do You Get It?

  • Melanoma begins in the melanocytes which are located in the lower part of the epidermis
  • Melanoma arises due to a combination of UV exposure and genetic susceptibility
  • Normal melanocytes transform into melanoma cells through a multi-step process of progressive genetic mutations that alter cell proliferation, differentiation, and death
  • A number of genetic mutations have been implicated in melanoma including: BRAF, NRAS, CDKN2A, CDK4, MC1R,  p16/ARF
    • Most are acquired, not inherited
  • Known risk factors for metastatic melanoma include:
    • Ultraviolet exposure
      • Sun exposure​
      • Tanning/artificial UV​
      • History of severe sunburn in childhood or adolescence​
      • Intermittent intense sun exposure
      • UV rays
      • A major cause of melanomas​
      • UV rays damage the DNA of skin cells​
    • Genetic predisposition
      • Family history of melanoma​
      • Fair skin, freckles, blue eyes
      • Light skinned people are at a higher risk than dark skinned people​
      • Many moles or atypical moles​
      • Xeroderma pigmentosum (XP) – a rare hereditary defect in which skin cells are not as able to repair damaged DNA
      • Gene changes
      • Most gene changes seen in melanoma are not inherited​
      • Melanomas that occur in areas of the body that are rarely exposed to sunlight often have different gene changes than those in melanomas that develop in sun-exposed areas​
      • Inherited melanomas most often have changes in tumor suppressor genes such as CDKN2A (also known as p16) CDK4 and p53​
      • The BRAF genetic mutation is found in about 50% of all melanoma​​
    • Older age
    • Male gender
    • Immunosuppression
      • Organ transplant recipients​
      • HIV​

What Are The Symptoms?

  • Around 25 percent of melanomas arise from moles
  • Early warning signs are critical to avoid metastatic melanoma. These can include:
    • Any change in a mole, blemish, freckle, birthmark, or pigmented area​
    • A new mole or freckle that appears out of the blue or is growing rapidly, especially if you don’t have many moles, or the new mole or freckle looks different from those you do have​
    • A change in surface texture or in the way a mole feels to the touch​
    • A new “freckle” that is dark, dry, or scaly​
    • A pigmented area or splotch that is new or that you don’t remember seeing before​
    • A new spot that is black, even if very small​
    • A mole or other spot that looks or behaves differently than those around it, even if it seems otherwise normal​
    • A mole or other spot that itches and/or bleeds​
    • Redness, other colors, or shadow extending into the surrounding skin​
  • Symptoms of metastatic melanoma that has spread can include:
    • Hardened lumps under your skin​
    • Swollen or painful lymph nodes​
    • Trouble breathing, or a cough that doesn’t go away​
    • Swelling of liver or loss of appetite​
    • Bone pain or, less often, broken bones​
    • Headaches, seizures, or weakness or numbness in arms or legs​
    • Weight loss​
    • Fatigue​
  • This cancer can spread to many places in the body. The most common areas include:
    • Lungs​
    • Liver​
    • Bones​
    • Brain​
    • Abdomen​
    • Lymph Nodes​
    • Subcutaneous tissue​
    • Less common sites include:​
      • Adrenal glands​
      • Spleen​
      • Gastrointestinal tract​
      • Heart

How Is It Treated?

  • Treatment recommendations depend on many factors, including:​
    • the thickness of the primary melanoma​
    • whether the cancer has spread​
    • the stage of the melanoma​
    • the presence of specific genetic changes in melanoma cells​
    • rate of melanoma growth​
    • the patient’s other medical conditions​
  • Early-stage melanomas can often be treated effectively with surgery alone​
  • Therapies can include:
    • Surgery
      • Metastatic melanoma is very unlikely to be curable by surgery​
      • Surgery is typically done to control metastatic melanoma, not to cure it​
      • If some metastatic areas can be removed, it may help prolong life​
      • Removing metastases in some areas, such as the brain, may alleviate symptoms and help improve quality of life​​
    • Immunotherapy(Biologic Therapy)
      • Immunotherapy: The use of medicines to stimulate a patient’s own immune system to recognize and destroy cancer cells more effectively
      • Immune checkpoint inhibitors – Target the checkpoints that melanoma cells use to avoid being attacked by the immune system
        • PD-1 inhibitors
          • Targets PD-1, a protein on the T cells. By blocking PD-1, these drugs boost the immune response against melanoma cells​
          • Given as an intravenous (IV) infusion every 2 or 3 weeks​
          • Have been shown to shrink melanoma for 30% to 40% of patients​
        • CTLA-4 inhibitor
          • Works by taking the brakes off the immune system. Targets a molecule called cytotoxic T-lymphocyte associated molecule-4 (CTLA4)​
          • Given IV once every 3 weeks for 4 treatment​
          • Clinical trials showed that people taking a CTLA-4 inhibitor had a better chance of survival than people who only received traditional chemotherapy​
        • Cytokines – Proteins in the body that boost the immune system in a general way​
          • Can help shrink advanced (stage III and IV) melanomas in about 10% to 20% of patients when used alone​
          • Can be used as an adjuvant therapy to prevent melanoma cells from spreading and growing​
    • Targeted therapy
      • A treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival​
      • Blocks the growth and spread of cancer cells while limiting damage to healthy cells​
      • Targeted therapies attack some of the gene changes that make melanoma cells different than normal cells​
      • Treatment is personalized based on the particular melanoma’s genetic abnormalities or mutations​
      • Types of targeted therapies include:
        • BRAF inhibitors
          • About half of all melanomas have mutations in the BRAF gene​
          • BRAF mutations cause the gene to make an altered BRAF protein that signals the melanoma cells to grow and divide quickly
          • Acquired resistance to BRAF inhibitors, typically sets in after 6 months of treatment​
          • More than ten resistance mechanisms have been identified so far including: NRAS mutations, BRAF amplification and splicing, MEK 1/2 mutations, KRAS mutations, as well as alteration in parallel signaling in PI3K/AKT signaling pathway​
          • The addition of a MEK inhibitor to a BRAF inhibitor is a widely practiced strategy for delaying BRAF inhibitor treatment-acquired resistance​
          • Other methods of reducing resistance are currently in early clinical trial​
          • Administered orally twice per day
            • Dabrafenib (Tafinlar)​
            • Vemurafenib (Zelboraf)​
        • MEK inhibitors
          • Targets the MEK protein, which is involved in cancer growth and survival​
          • The MEK gene is in the same signaling pathway inside cells as the BRAF gene, so drugs that block MEK proteins can also help treat melanomas with BRAF gene changes
          • Administered orally once per day
            • Trametinib (Mekinist)​​
        • KIT inhibitors
          • Mutated in increased numbers in certain subtypes of melanoma including lentigo maligna melanoma, mucosal melanoma, and acral lentiginous melanoma​
        • Combination of BRAF and MEK inhibitors
          • Is thought to delay the emergence of resistance compared with singe-agent BRAF inhibitors​
    • Chemotherapy
      • Chemotherapy is no longer first-line therapy for advanced melanoma since the arrival of immunotherapy and targeted drugs​
      • Chemotherapy is usually not as effective in melanoma as other cancers but can relieve symptoms or extend survival for some patients​
      • Typical chemotherapy drugs used in melanoma include:
        • Dacarbazine (DTIC-Dome) – The only FDA approved chemotherapy for melanoma
        • Temozolomide (Methazolastone, Temodar)​
        • Cisplatin (Platinol)​
        • Carmustine (also known as BCNU)​
        • Fotemustine (Muphoran)​
        • Lomustine (CeeNU)​
        • The taxanes (a group of drugs that includes docetaxel [Taxotere] and paclitaxel [Taxol]), nab-paclitaxel [Abraxane], and vinblastine (Velban, Velsar)​
        • Combinations of chemotherapy drugs, such as paclitaxel plus carboplatin or cisplatin combined with vinblastine and DTIC may be used
    • Radiation therapy
      • There are several ways radiation therapy may be used in metastatic melanoma​
      • When cancer has extensive spread to the lymph nodes, following a lymph node dissection​
      • When the amount of melanoma that can be removed with surgery is limited by the location of the tumor​
      • Palliative radiation therapy
        • Used to relieve symptoms such as bone pain or headache​
        • Can be given to an entire organ or using  stereotactic ablative radiation therapy​
    • Intralesional therapy
      • Talimogene laherparepvec (TVEC) is injected directly into one or more melanoma tumors​
      • TVEC is a herpes virus designed in a laboratory to make an immune-stimulating hormone. This virus can infect and destroy melanoma cells.​
      • TVEC also helps stimulate the immune system to destroy other melanoma tumors​
      • Clinical trials are ongoing​
    • Isolated limb infusion therapy
      • Used if there are too many tumors in one arm or leg for surgery to be feasible or helpful​
      • A tourniquet is placed on the arm or leg and then high doses of chemotherapy are given. The tourniquet keeps the chemo in the limb and prevents it from being transported throughout the body​
      • 50-80% of tumors respond though typically it is temporary​​
    • Researchers are testing the effectiveness of chemoradiation, a combination of radiation therapy and chemotherapy
    • The brain is one of the most common places melanoma spreads​
    • The presence of brain metastases is linked with a very poor prognosis​
    • It is difficult to get chemotherapy drugs into brain tissue​
    • The following treatments may be recommended for melanoma that has spread to the brain:
      • Radiation
      • BRAF inhibitors
      • Immunotherapy​

Where Can I Learn More???

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