Melanoma: Follow-Up Fine Points

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Post-treatment follow-up for melanoma consists of a combination of standard recommendations that apply to all melanoma cases, as well as those that are stage-specific. Additionally, oncologists may have patient-specific recommendations, depending on disease characteristics.

General Recommendations

The National Comprehensive Cancer Network recommends the following for all melanoma patients:

• A complete history and physical exam, at least annually; optionally, total-body photography, sequential digital dermoscopy, and other imaging techniques can provide a baseline body-surface landscape to aid monitoring for recurrence or new melanoma lesions

• Ongoing patient education related to skin and lymph node self-examination and principles of sun safety

• The follow-up interval/schedule should be influenced by the risk of recurrence and the appearance of any new primary melanoma; patient/family history, mole count, and presence or history of atypical moles/dysplastic nevi also influence follow-up

• For patients with an equivocal lymph node exam, short-term follow-up or additional imaging (preferably ultrasound) should be considered, followed by imaging-directed biopsy, if indicated

• Regional lymph node ultrasound for patients who had a positive sentinel lymph node biopsy but did not have a complete lymph node dissection, if appropriate expertise is available; preferably, ultrasound evaluation should occur every 4 months during the first 2 years, then every 6 months for years 3 through 5

• Clinical and family history can help identify patients for whom multigene testing might determine an increased genetic risk for cutaneous and uveal melanoma and other types of cancer. Genetic information also can guide surveillance recommendations. Consider referral for genetic counseling if a patient has a history of more than one malignancy or a strong family history of malignancies including melanoma, breast, renal, or pancreatic cancer. Patients may need testing to include CDK4, MC1R, BRCA2, BAP1, TERT, MITF, and PTEN. If a patient has three or more invasive cutaneous melanomas or a mix of melanoma, pancreatic cancer, and/or astrocytoma (or a family history), p16/CDKN2A mutation testing may be indicated. Multigene testing that includes CDKN2A also is recommended for patients who have a first-degree relative with a history of pancreatic cancer. Testing for other genes that can harbor melanoma-predisposition mutations might be warranted

Stage-Specific Follow-Up

General recommendations for all patients, as outlined above, apply to follow-up, regardless of the stage of the patient's index melanoma. The overarching emphasis is on monitoring for recurrence or new lesions.

Stage 0 (in situ)

In general, these patients require limited investigation beyond the history and physical exam. Annual follow-up visits are appropriate in most cases. Routine laboratory tests or imaging to screen for asymptomatic recurrence or metastasis is not recommended.

Stage IA-IIA (NED)

These recommendations apply to patients who have no evidence of disease (NED) after treatment. The history and physical exam should focus on the skin and lymph nodes. Follow-up should occur every 6 to 12 months for 5 years, and then annually as indicated by risk status. Routine blood tests and imaging are not recommended. Selective use of imaging is appropriate to investigate specific signs or symptoms.

Stage IIB-IV (NED)

Patients should have a history and physical exam every 3 to 6 months for 2 years, and then every 3 to 12 months for 3 years. Thereafter, annual visits are appropriate but can occur at shorter intervals as indicated by risk factors. Routine laboratory testing is not recommended.

In general, imaging should be used as indicated to investigate specific signs or symptoms. Depending on a patient's individual circumstances and physician preference, imaging every 3 to 12 months for 2 years and then every 6 to 12 months might be considered (unless mandated by participation in a clinical trial). Routine imaging to screen for asymptomatic recurrence or metastatic disease is not recommended after 3 to 5 years.

Unresectable/Metastatic Disease

For patients with unresectable or metastatic disease, the focus of follow-up switches from monitoring for recurrence/new lesions to monitoring of toxicities and for disease progression. Follow-up is individualized and guided by a patient's ongoing treatment. The frequency of visits, types of tests, and use of imaging will depend on the type of treatment and the patient's response. Monitoring should include the patient's need for symptom management, supportive care, and palliative treatment.

Managing Side Effects

Educate patients about potential long-term and late side effects to local and systemic therapy. Patients may be unaware that side effects can continue after treatment ends or can arise months or even years later. Review potential side effects with patients at each follow-up visit, educate them about how to recognize long-term and late side effects, and encourage them to report new or worsening side effects that occur between visits.

For patients who have thicker melanomas that require a skin graft, pain may persist and post-treatment rehabilitation might be required in some instances.

The treatment landscape for melanoma has changed dramatically over the past 10 to 15 years. Treatment no longer relies on cytotoxic chemotherapy but rather on targeted agents and immunotherapy. These newer treatments have different side-effect profiles as compared with chemotherapy, and some effects can persist long term, particularly with immune therapy. Commonly used targeted therapies have some overlapping toxicities but also different ones.

BRAF Inhibitors

Currently approved drugs in this class are vemurafenib (Zelboraf), dabrafenib (Tafinlar), and encorafenib (Braftovi). Common side effects associated with these drugs include rash, itching, sensitivity to the sun, headache, fever, joint pain, fatigue, hair loss, and nausea.

Serious but less common side effects include cardiac arrhythmias, liver problems, kidney failure, severe allergic reactions, severe skin or eye problems, bleeding, and increased blood sugar levels. When administered alone, the drugs can cause nonmelanoma skin cancer, a risk that is minimized by taking combination treatment with a BRAF inhibitor and a MEK inhibitor.

MEK Inhibitors

Approved drugs in this class are trametinib (Mekinist), binimetinib (Braftovi), and cobimetinib (Cotellic). Side effects include rash, nausea, diarrhea, edema, and sunlight sensitivity. Rarely, MEK inhibitors cause serious side effects that include cardiac, pulmonary, and liver toxicities; bleeding or blood clots; vision problems; muscle damage; and skin infections.

For melanoma treatment, drugs in this class are always combined with a BRAF inhibitor. Approved combinations consist of dabrafenib/trametinib, encorafenib/binimetinib, and vemurafenib/cobimetinib. Some side effects occur less often with a combination than with the individual drugs -- most notably, nonmelanoma skin cancer.

Immune Checkpoint Inhibitors (Immunotherapy)

The anti-PD1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) and the CTLA-4 inhibitor ipilimumab (Yervoy) are approved for treatment of melanoma. Additionally, the combination of nivolumab and ipilimumab has FDA approval for melanoma, as does nivolumab plus the LAG-3 inhibitor relatlimab (a combination known as Opdualag).

Immune checkpoint inhibitors cause adverse effects (AEs) specific to manipulation of the immune system (immune-related AEs, irAEs). In clinical studies of melanoma, the most common irAEs associated with nivolumab and pembrolizumab were hypothyroidism, diarrhea, pruritus, rash, and arthralgias; less commonly, the drugs were associated with pneumonitis, colitis, and vitiligo. In trials with ipilimumab, common irAEs included pruritus, diarrhea, hepatitis, and rash. Mild side effects can be managed while continuing treatment; however, more severe side effects require holding or permanently stopping treatment and starting high-dose steroids. Side effects are usually reversible, however. Severe and fatal irAEs have been reported in some instances, including neurotoxicity, cardiotoxicity, and pulmonary toxicity. Additionally, irAEs can persist long term in some patients, requiring ongoing treatment with immune suppression with steroids or other medications.

Read previous installments in this Medical Journeys series:

Part 1: Melanoma: Epidemiology, Diagnosis, and Treatment

Part 2: Recognizing Melanoma: What It Is, What It Isn't

Part 3: Basics of Melanoma Diagnosis

Part 4: Case Study: The Dangers of Melanoma Recurrence

Part 5: Managing Early-Stage Melanoma

Part 6: Managing Unresectable/Metastatic Melanoma: What to Know

Part 7: Case Study: Did This Melanoma Metastasize or Is It Something Else?

Part 8: Sorting Through Therapeutic Options for Advanced Melanoma

Part 9: Recurrent Melanoma: Navigating the Clinical Pathways