Melanoma: An FP’s guide to diagnosis and management

Systemic melanoma treatment and common adverse effects

Multiple systemic therapies have been approved for the treatment of advanced or unresectable cutaneous melanomas. While these treatments are managed primarily by Oncology in concert with Dermatology, an awareness of the medications’ common dermatologic toxicities is important for the primary care provider. The 2 broad categories of FDA-approved systemic medications for advanced melanoma are mitogen-activated protein kinase (MAPK) inhibitors and immune checkpoint inhibitors, each having its own set of adverse cutaneous effects.

MAPK pathway–targeting drugs include the B-Raf proto-oncogene serine/threonine-kinase inhibitors (BRAFIs) vemurafenib and dabrafenib, and the MAPK inhibitors (MEKIs) trametinib and cobimetinib. The most common adverse skin effects in MAPK pathway–targeting drugs are severe ultraviolet photosensitivity, cutaneous epidermal neoplasms (particularly squamous cell carcinoma, keratoacanthoma-type), thick actinic keratosis, wart-like keratosis, painful palmoplantar keratosis, and dry skin.³⁸ These effects are most commonly seen with BRAFI monotherapy and can be abated with the addition of a MEKI. MEKI therapy can cause acneiform eruptions and paronychia.³⁹ Additional adverse effects include diarrhea, pyrexia, arthralgias, and fatigue for BRAFIs and diarrhea, fatigue, and peripheral edema for MEKIs.⁴⁰

Immune checkpoint inhibitors include anti-CTLA-4 (ipilimumab), anti-PD-1 (pembrolizumab and nivolumab), and anti-PDL-1 (atezolizumab). Adverse skin effects include morbilliform rash with or without an associated itch, itch with or without an associated rash, vitiligo, and lichenoid skin rashes. PD-1 and PDL-1 inhibitors have been associated with flares or unmasking of atopic dermatitis, psoriasis, sarcoidosis, and autoimmune bullous disease.¹⁸ Diarrhea, colitis, hepatitis, elevated liver enzymes, hypophysitis, and thyroiditis are some of the more common noncutaneous adverse effects reported with CTLA-4 inhibitors, while fatigue, diarrhea, nausea, pneumonitis, and thyroid disease are seen with anti-PD-1/PDL-1 therapy.³

A look at the prognosis

For patients diagnosed with primary cutaneous melanoma between 2011 and 2017, the 5-year survival rate for localized disease (Stages I-II) was 99%.¹ For regional (Stage III) and distant (Stage IV) disease, the 5-year survival rates were 68% and 30%, respectively.¹ With the advent of adjuvant systemic therapy, 5-year overall survival rates for metastatic melanoma have markedly improved from < 10% to up to 40% to 50%.⁴¹ The 3-year survival rate for patients with high tumor burden, brain metastasis, and elevated lactate dehydrogenase remains at < 10%.⁴² Relative survival decreases with increased age, although survival is higher in women than in men.⁴³ Risk of melanoma recurrence after surgical excision is high in patients with stage IIB, IIC, III and IV (resectable) disease. The most important risk factor for recurrence is primary tumor thickness.⁴⁴ The most common site of first recurrence in stage I-II disease is regional lymph node metastasis (42.8%), closely followed by distant metastasis (37.6%).⁴⁴

Long-term follow-up and surveillance

Recommendations for long-term care of patients with melanoma have evolved with advances in treatment, prognostication, and imaging. Caring for these patients requires a multidisciplinary approach wherein the family physician provides frontline care and team coordination. Since most recurrences are discovered by the patient or the patient’s family, patient education and self-examination are the cost-effective foundation for recurrence screening. In a trial of patients and partners, a 30-minute structured session on skin examination followed by physician reminders every 4 months increased the detection of melanoma recurrence without significant increases in patient visits.⁴⁵

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