— Wide excision, adequate margins, options for adjuvant therapy
Reviewed By Meredith McKean, MD, MPH, clinical investigator, Melanoma and Skin Cancer Research Program, Sarah Cannon Research Institute, Tennessee Oncology, Nashville
Surgery forms the basis of treatment for early-stage melanoma, which includes stages I and II and most stage III disease. In many instances, surgery is the only treatment recommended when the risk of regional or metastatic disease is low and surgical resection is performed with curative intent. Patients with oligometastatic disease may also be candidates for surgical resection. Adjuvant therapy is offered for an expanding list of indications, now including surgically resected stages II, III, and IV disease. Systemic therapy becomes the primary treatment modality if stage III or even stage IV disease is considered unresectable. Characteristics of both the primary tumor and sites of regional metastasis can impact treatment planning including surgical and medical options.
Across the range of early-stage disease, the risk of metastatic progression increases with melanoma thickness. The thickness of a lesion at diagnosis has implications: whether sentinel lymph node biopsy (SLNB) is pursued, surgical planning, and consideration of systemic therapy.
Even among so-called “thin” melanomas (≤1 mm), thinner is better. In the latest National Comprehensive Cancer Network (NCCN) guidelines for melanoma, multiple studies from 2001 to 2013 showed a 5.3% rate of SLNB positivity in association with thin melanomas. However, further subdivision of thin melanomas showed that 2.9% of lesions <0.75 mm were associated with a positive SLNB as compared with 7.1% for lesions with a thickness of 0.75-1.0 mm.
In general, SLNB is pursued when the risk is >10% for a positive SLNB, >1 mm. SLNB can be pursued for thinner melanomas based on individual patient risk factors after discussion with a surgeon.
As of 2021, adjuvant therapy is now offered to some patients based on the primary tumor depth alone. Patients with stage IIB/C disease, which includes patients with primary tumor thickness of >2 mm with ulceration or >4 mm without ulceration now have an indication for adjuvant pembrolizumab to decrease their risk of recurrence.
Typically, wide excision refers to surgery that includes a surgical margin of at least 1 cm around the excised lesion. A large international study of patients with melanomas ≤2 mm thick showed no difference in disease recurrence, disease-free survival, or overall survival with a surgical margin of 1 vs ≥3 cm. A European study involving patients with melanomas ≥2 mm thickness showed that wide excision with surgical margins of 2 or 4 cm led to similar 5-year overall survival, and a subsequent meta-analysis showed that margins of 1 to 2 cm are adequate for thicker melanomas. Excision margins increase with lesion thickness, up to >4 mm with 2 cm margins.
SLNB is a minimally invasive staging procedure for patients with melanomas >1 mm or thinner lesions with additional risk factors. It is almost always performed at the same time as wide excision of the primary tumor. This procedure helps determine patients who may have subclinical regional lymph node involvement and then meet criteria for stage III disease.
Use of SLNB alone does not affect patient survival, but can indicate higher-risk disease and provide an indication for adjuvant systemic therapy.
Completion regional lymph node dissection is no longer indicated for patients with positive sentinel lymph node alone if they undergo serial lymph node basin ultrasound. Patients may otherwise pursue completion lymph node dissection for positive sentinel lymph node, multiple involved lymph nodes, or clinically positive lymph node metastases.
Stage 0 (in situ)
Patients with melanoma in situ can be managed adequately with surgical excision that results in microscopically free margins around the tumor bed. SLNB is not recommended.
If surgery is undesirable or not feasible because of location or considerations related to cosmesis, topical imiquimod offers an alternative to surgery, particularly for lentigo maligna. Studies reviewed by NCCN showed histologic clearance rates of 70-100% and recurrence rates of 0-4%, which were generally consistent across the studies.
Second-line or adjuvant imiquimod also is an option when surgery results in narrow margins. Long-term comparative studies with surgery alone have yet to be conducted.
Stage I
In general, the NCCN recommends wide excision without SLNB for patients with stage IA or IB melanoma lesions that are ≤0.75 mm thick, except when uncertainty exists about microstaging. Conventional risk factors (high mitotic rate, ulceration, or lymphovascular invasion) are uncommon in such thin melanomas.
SLNB might warrant consideration for stage IA lesions 0.76-1.00 mm thick without ulceration and with a mitotic rate of 0 per mm2. As a rule, SLNB should be offered to patients with higher-risk stage IB melanomas, defined as thickness >1 mm or thickness 0.76-1.0 mm with ulceration or mitotic rate ≥1 mm2.
Stage II
Wide excision with a clear margin is standard treatment for stage II melanoma. SLNB is not universally recommended, but many oncologists and dermatologists do recommend it, depending on the risk associated with the lesion and the level of suspicion regarding lymph node involvement. If an SLNB is negative, no further surgery is required. A positive SLNB upgrades a melanoma to stage III.
Some clinicians recommend adjuvant pembrolizumab (Keytruda) after excision of certain types of stage II melanoma to minimize the risk of recurrence. The U.S. Food and Drug Administration approved pembrolizumab as adjuvant therapy for stages IIB and IIC melanoma on the basis of a placebo-controlled clinical trial that showed a 35% reduction in the risk of recurrence among patients who received the immune checkpoint inhibitor (ICI).
The NCCN does not support adjuvant systemic therapy for stages I/II melanoma outside of the setting of a clinical trial, but acknowledges that the clinical rationale for adjuvant therapy varies. The National Cancer Institute considers current data inadequate to make a definitive judgment about the use of adjuvant systemic therapy and encourages clinicians to consider enrolling patients in ongoing clinical trials.
Stage III
Stage III melanoma, by definition, means the cancer has spread beyond the primary tumor to regional lymph nodes or is in transit toward the regional nodal basin.
Stage III melanoma comprises four subgroups or subcategories (A-D) with each subsequent letter corresponding to higher risk. The subgroups take into account a variety of factors, such as the size and depth of the primary tumor, number of involved lymph nodes, presence or absence of ulceration, and mitotic rate.
Basic treatment consists of wide total excision of the primary tumor and involved lymph nodes (or detectable nodules in the case of in-transit melanoma). NCCN guidelines allow for omission of complete lymph node dissection in favor of surveillance with nodal ultrasound at the clinician’s discretion for patients with lymph node involvement limited to a positive sentinel lymph node.
Multiple FDA-approved drugs have been evaluated as adjuvant therapy for stage III melanoma, including ICIs and targeted agents. Currently, only three therapies have NCCN endorsement as adjuvant treatment for resected stage III melanoma: pembrolizumab, nivolumab (Opdivo), and the combination targeted therapies dabrafenib/trametinib (Tafinlar/Mekinist). FDA approval of dabrafenib/trametinib is limited to melanoma associated with BRAF V600E or V600K mutations, which occur in about half of all melanomas.
Several clinical trials have shown benefits with neoadjuvant therapy for resectable high-risk stage III disease. The NCCN currently does not recommend neoadjuvant therapy outside the setting of a clinical trial.
In some cases, complete wide excision might not be feasible or a previous excision might have been unsuccessful or a patient might have declined to have surgery. Several options exist for local treatment in those situations.
Intralesional Injections
Talimogene laherparepvec (T-VEC, Imlygic) is an injectable therapy available for patients with locally advanced disease. In a phase III randomized trial, T-VEC induced clinically significant and durable responses in injected tumors and produced significantly higher durable response and overall response rates as compared with subcutaneous granulocyte macrophage colony-stimulating factor.
Topical Therapy
Case series have suggested that topical imiquimod can produce partial or complete responses for in-transit or locally advanced melanoma, primarily for lesions that do not have deep dermal or subcutaneous penetration. Multidisciplinary discussion and consideration of all treatment modalities would be encouraged prior to pursuing topical therapy alone for locally advanced disease.
Local Ablation
Laser ablation of thin lesions has been documented in multiple noncomparative retrospective analyses involving 100 or fewer patients. Though ablation can be achieved with minimal toxicity, the technique has mostly been supplanted by more contemporary strategies.
Overall, adjuvant radiation therapy has a limited role in the management of early-stage melanoma following successful wide excision of the primary tumor. One possible exception is desmoplastic neurotropic melanoma, a locally aggressive subtype. Adjuvant radiation therapy has been shown to reduce local recurrence of pure desmoplastic melanoma.
Adjuvant radiation therapy also should be considered on a case-by-case basis for preventing nodal recurrence. Compelling evidence indicates that adjuvant radiation therapy can delay or prevent nodal relapse in high-risk patients, but a risk of late radiation-related toxicity and a lack of survival benefit (possibly a trend toward worse survival) should be taken into account in the decision-making process.
Read previous installments in this 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
