Continuing Education Activity

Melanoma is the third most common cutaneous malignancy after basal cell carcinoma and squamous cell carcinoma. Melanoma is the fifth most common malignancy in males and sixth most common malignancy in females. While most melanomas are detected at an early stage, a proportion of patients have metastatic disease at the time of diagnosis or develop metastasis at a later stage. Skin and subcutaneous tissue followed by lungs, liver, bones, and brain are the most common sites of metastasis. The treatment paradigm of metastatic melanoma has changed dramatically within the last few years with the advent of immune checkpoint inhibitors and targeted therapy. The treatment modalities that are currently used for metastatic melanoma include surgery, immunotherapy, targeted therapy, and chemotherapy. This activity explains when metastatic melanoma should be considered on a differential diagnosis, articulates how to properly evaluate for this condition, and highlights the role of the interprofessional team in caring for patients with this condition.

Objectives:

• Describe the evaluation of a patient with suspected metastatic melanoma.
• Contrast the roles of the various modalities of treatment for metastatic melanoma such as surgery, radiation, and chemotherapy.
• Explain the role of immune checkpoint inhibitors and BRAF targeted therapy for melanoma.
• Outline a well-coordinated, interprofessional team approach to provide effective care to patients affected by metastatic melanoma.

Introduction

According to the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, the rates of melanoma have been trending up over the past few decades. In fact, it is the 5th most common type of cancer, representing 5.6% of all new cancer cases in the United States. It is commonly diagnosed among people of fair complexion and those who have been exposed to natural or artificial sunlight (such as tanning beds) over a prolonged period of time.

Etiology

Certain types of melanoma are associated with cumulative solar damage (CSD). However, in some cases, the etiology is not always clear.[1] The 2018 WHO Classification of Melanoma categorizes melanomas into:

A. Melanomas typically associated with CSD

Pathway I. Superficial spreading melanoma/low-CSD melanoma

Pathway II. Lentigo maligna melanoma/high-CSD melanoma

Pathway III. Desmoplastic melanoma

B. Melanomas not consistently associated with CSD damage

Pathway IV. Spitz melanomas

Pathway V. Acral melanoma

Pathway VI. Mucosal melanomas

Pathway VII. Melanomas arising in congenital nevi

Pathway VIII. Melanomas arising in blue nevi

Pathway IX. Uveal melanoma

C. Nodular melanoma (may occur in any or most of the pathways)

Epidemiology

According to the SEER program, it is estimated that 100,350 new cases of melanoma of the skin may be diagnosed in the United States in 2020. It is more common in men than in women, and most frequently diagnosed among people aged 65 to 74. At diagnosis, localized disease (confined to primary site) accounts for 83% of cases, followed by regional disease (spread to regional lymph nodes) in 9% of cases, distant metastatic disease in 4% of cases, and unstaged in 4% of cases.

Pathophysiology

The majority of melanomas arise from melanocytes in the epidermis.[1] There are 2 major stages of progression. In the radial growth phase, the tumor cells expand along the radii of an imperfect circle in the horizontal axis within the skin. In the next stage of progression, called the vertical growth phase, the tumor cells may infiltrate into the dermis or elevate the epidermis to form a nodule. These lesions have a potential to metastasize.

History and Physical

The characteristic signs of early melanoma are recognized with the well-known ABCDE mnemonic as follows:[2]

• “A” stands for Asymmetry
• “B” stands for Border: irregular, ragged, notched, or blurred edges
• “C” stands for Color: nonuniform
• “D” stands for Diameter: larger than 6 millimeters
• “E” stands for Evolving: changing in size, shape, or color

Depending on the site of metastases, the clinical presentation may vary.

Evaluation

The disease should be confirmed pathologically by using fine-needle aspiration biopsy, core biopsy, excisional, or incisional biopsy depending on the disease's location.[3] For baseline staging, whole-body positron emission tomography/computed tomography (PET/CT) may be superior to CT with contrast of the chest, abdomen, and pelvis.[4] Magnetic resonant imaging (MRI) with contrast of the brain may be considered for brain metastases.

BRAF mutation testing is crucial as BRAF-targeted therapy may be considered if the disease harbors a BRAF V600-activating mutation.[5] Serum lactate dehydrogenase carries a prognostic value and should be obtained at diagnosis of stage IV disease.[3]

Treatment / Management

Management of metastatic melanoma depends on whether disease is resectable (limited) or unresectable (disseminated).[3] Resection or systemic therapy may be considered for limited metastatic melanoma. For disseminated melanoma, treatment depends on the location and extent of the disease. Options include systemic therapy, local therapy, clinical trial, or supportive care.

Systemic Therapy

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors have been shown to be effective regardless of BRAF mutation status.[6][7][8][9] Options include nivolumab, pembrolizumab, or nivolumab/ipilimumab combination therapy. Nivolumab and pembrolizumab are the programmed cell death protein 1 (anti-PD-1) antibodies that interfere with ligand binding by the T-cell surface receptor PD-1, enhancing T-cell activation. Ipilimumab is a monoclonal antibody that binds and blocks the function of the immune checkpoint receptor CTLA-4.

BRAF/MEK Inhibitor Combination Therapy

BRAF-targeted therapy may be considered if the disease harbors a BRAF V600-activating mutation. Results from multiple randomized trials suggest that BRAF/MEK inhibitor combination therapy may enhance duration of response compared with BRAF inhibitor monotherapy.[10][11][12][13][14][15][16][17] The combination therapy includes dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib.

It is important to note that BRAF inhibitors and MEK inhibitors may interact with radiation therapy and have a potential for increased toxicity.[18][18] Therefore, it is recommended to hold these medications for 1 or more day before and after stereotactic radiosurgery (SRS) and 3 or more days before and after fractionated stereotactic radiation therapy (SRT).

Local Therapy

Local therapy options for extracranial metastases include intralesional injection with talimogene laherparepvec (T-VEC), resection, or radiation.[3] Radiation therapy may be used as palliative management of visceral, bone, and CNS metastases. For patients with brain metastases, SRS and/or whole brain radiation therapy (WBRT) may be considered as the primary modality or as an adjuvant following surgical resection.

Follow-Up

The frequency of follow-up should be individualized.[3] Generally, chest x-ray, CT, brain MRI and/or PET/CT can be considered to screen for recurrent disease. For patients with prior brain metastases, more frequent surveillance with brain MRI is recommended.

Supportive Care

For those with very poor performance status, disease progression despite proper treatment, or not fit for the preferred systemic treatment options, supportive care may be considered.[3]

Differential Diagnosis

The differential diagnoses include basal cell skin cancer, squamous cell skin cancer, Merkel cell carcinoma, and dermatofibrosarcoma protuberans.

Staging

The American Joint Committee on Cancer (AJCC) TNM system is the staging system most often used for melanoma.[19] It is also known as the pathologic stage or the surgical stage, and is based on the extent of the primary tumor (T), the spread to nearby lymph nodes (N), and the spread to distant sites (M). Patients may also be staged clinically as follows:

• Stage 0: in-situ melanoma
• Stage I-II: invasive melanoma and clinically negative nodes
• III: palpable regional nodes, in-transit disease or microsatellites
• IV: distant metastases

Prognosis

According to the SEER program, those with distant metastatic disease have a 5-year survival rate of 27.3%.

Complications

Timely recognition and proper management of the potential treatment-related complications are crucial to alleviate morbidity and mortality among the patients.

Deterrence and Patient Education

Being diagnosed with metastatic melanoma and undergoing treatment can affect the emotional health of patients and their families, as their physical, spiritual, emotional, and interpersonal dimensions can be dramatically changed. Managing the psychological effects can be crucial to ensuring longer survivorship. Therefore, screening and assessment of emotional and social concerns of patients and their families should be included in every follow-up visit. Patients should be well-educated on the management plan including the types of treatment, pros and cons of each treatment, side effects, and supportive measures. Counseling, referring the patients to the support groups, collaborating with the mental health professionals, can also be considered. Regular follow-up with oncologists and primary care physicians is also essential in monitoring treatment response and treatment-related toxicities.

Enhancing Healthcare Team Outcomes

Patient-centered team-based care play a vital role in managing patients with metastatic melanoma. Well-implemented team-based care has the potential to improve the comprehensiveness, efficiency, effectiveness, coordination, and value of care in every step of management from evaluation and diagnosis of the disease, to management of complications related to disease or treatment, as well as regular follow-ups, and psychosocial support.