It is no coincidence that May is Melanoma Awareness Month. As Americans take to the great outdoors, they also must take caution to protect their skin and prevent melanoma.
Melanoma is not the most common type of skin cancer, but it is the most aggressive and likely to metastasize. The American Cancer Society estimated 100,000 new diagnoses of melanoma in the United States in 2020 and about 7,000 deaths. The average age at diagnosis is 65, but melanoma is one of the most common cancers in young adults.
Prevention and Screening
Although it has no primary prevention measures, following certain lifestyle behaviors may reduce risk:
- Limit exposure to ultraviolet rays by using sunscreen, seeking shade, and staying indoors mid-day when the sun’s intensity is highest. Children are especially vulnerable to sunburn and should use extra sun protection
- Avoid using tanning beds and sunlamps.
- Watch for skin changes and report abnormal or changing moles or skin marks.
Skin assessment and screening is an important part of self-care. Annual physicals help with early identification of skin changes and skin malignancies, including melanoma.
Somatic mutations in BRAF gene lead to unrestrained cell growth and proliferation and prevention of apoptosis occurring in about 50% of melanomas (National Comprehensive Cancer Network, 2019). Accurate determination of the BRAF mutation status in melanoma tumor samples is critical because the efficacy of targeted therapy is restricted to patients whose tumors harbor activating BRAF mutations. BRAF V600 mutations are also sensitive to MEK1 inhibitors and should be combined with a BRAF inhibitor.
Approximately 10% to15% of acral and mucosal melanomas have been found to express mutations in c-KIT, a transmembrane tyrosine kinase receptor. Specific C-Kit mutations guide selection of targeted treatment. Mutations in exons 11 and 13 have a high level tyrosine kinase receptors whereas mutations in exon 17 and amplification of the c-KIT do not typically respond to tyrosine kinase inhibitors.
Mutations in NRAS have been found in approximately 15% of cases of melanoma. Tumors expressing NRAS mutations rarely co-express BRAF mutations but some will respond to an MEK1 inhibitor.
For local disease, surgery and radiation are used alone or in combination, with radiation given in the adjuvant setting after surgery to prevent recurrence. Until recently, systemic treatment methods such as chemotherapy weren’t successful in controlling metastatic melanoma. However, advancements in targeted therapies and immunotherapy are changing the landscape of melanoma treatment. Up to half of all metastatic melanomas express a mutated BRAF gene targeted by BRAF inhibitors. MEK inhibitors, especially in combination with BRAF inhibitors, are also prolonging survival and preventing recurrence.
Immunotherapy literally revolutionized melanoma treatment and significantly improved outcomes andsurvival rates. Checkpoint inhibitor therapy, interleukins, and cancer vaccines have all been approved for metastatic melanoma. Dual checkpoint inhibitor therapy—combining a PD-1 inhibitor with a CTLA-4 inhibitor—optimizes tumor shrinkage compared to a single checkpoint inhibitor, but adverse events are more prevalent and severe with combination treatments. Interleukin-2 is the longest-standing approved immunotherapy for melanoma, although frontline use is dwindling as more agents with less-aggressive side-effect profiles are approved with promising results.
Talimogene laherparepvec, also known as T-VEC, is an oncolytic virus used to treat nonresectable lesions. Injecting genetically modified viruses directly into cancer lesions helps the immune system identify and target malignant cells. Because administration involves injection of a live virus, healthcare providers must strictly adhere to precautions and administration policies to prevent shedding.
Side Effects and Management
Radiation therapy effects will be seen at the site of treatment. BRAF inhibitors can cause skin changes, fever joint pain, fatigue, and renal and hepatic toxicities, and MEK inhibitors are associated with rash, nausea, diarrhea, and heart, lung, and liver toxicities.
Checkpoint inhibitors are highly associated with fatigue and immune-related adverse events (irAEs), including colitis, dermatitis, pneumonitis and endocrinopathies. With the exception of endocrinopathies, early identification and management is usually effective in reversing the side effects and keeping patients on therapy.
Melanoma survivors are at high risk for additional lesions and recurrence and must receive regular skin and lymph node exams. As with other disease sites, survivorship care must also include prevention and screening for other primary cancers and healthy lifestyle choices surrounding diet, physical activity, and tobacco and alcohol use.
Patients who are treated with immunotherapy are subject to immune-related changes for years after treatment. Clinicians should be assessing for inflammatory changes in all organ sites and consider long-term immune changes as a possible cause.