Management strategy

Early detection of melanoma is paramount in its management. Physicians and patients must become familiar with the ABCDE signs of melanoma: asymmetry, border irregularity, color variegation, diameter >6 mm, and evolution. A specificity of 88% and sensitivity of 73% has been reported if two out of three of the following characteristics are noted on physical exam: irregular outline, diameter >6 mm, and color variegation. Even expert clinicians misdiagnose melanoma in up to one-third of cases, and only biopsy and histologic examination can provide a definitive diagnosis.

Important in the management of melanoma is primary prevention (risk reduction) and secondary prevention (early detection). Educating the public about the risks of sun exposure is a crucial part of primary prevention. Secondary prevention involves teaching high-risk patients about the ABCDE signs and how to perform total body self-examinations. The NIH stresses the importance of screening programs and regular skin examinations by health professionals. The American Academy of Dermatology Task Force recommends follow-up one to four times a year for 2 years after a diagnosis of melanoma, depending on the thickness of the lesion and other risk factors, such as a family history of melanoma, and then once or twice a year thereafter. Other modalities such as dermoscopy and the recently FDA-approved MelaFind are non-invasive tools aiding in identification of high-risk pigmented lesions.

The first step in the diagnosis of suspected melanoma is to obtain a biopsy. The ideal biopsy of a suspected primary cutaneous melanoma is a full-thickness excision with at least a 2 mm margin of normal-appearing surrounding skin to ensure that the lesion is not transected. If total excision is not practical, a full-thickness incisional biopsy usually suffices.

Staging of melanoma is crucial because it not only assigns patients into well-defined risk groups, it also aids in clinical decision-making as reviewed in the latest National Comprehensive Cancer Network (NCCN) clinical practice guidelines on melanoma. The goal of surgical management of primary cutaneous melanoma is to achieve negative histological margins to prevent recurrence and metastases. The current surgical margin guidelines from the NCCN are based on Breslow depth (Table 143.1). The standard treatment for stage IA melanoma is wide local excision. Total excision of primary melanoma with wide margins offers the best chance for cure. However, melanoma cells may extend non-contiguously for several millimeters beyond the visible lesion.

The NCCN suggests that sentinel lymph node (SLN) biopsy be discussed and offered to patients in those with melanomas at least 1 mm thick, or with ulceration or additional adverse features. The SLN is detected by preoperative lymphoscintigraphy followed by intraoperative injection of a dye and/or a radiocolloid around the primary lesion. The presence of melanoma in the SLN is the most significant factor in the prognosis of a patient with localized cutaneous melanoma undergoing SLN biopsy. If the SLN is histologically positive, a selective lymphadenectomy is recommended. The overall effect of selective lymphadenectomy following a positive SLN has yet to show survival benefit. An elective lymphadenectomy may also be performed, which involves removal of regional lymph nodes without preceding clinical or microscopic evidence of nodal metastases. This procedure, which results in significant morbidity, remains controversial.

For patients with stage III melanoma, the number of positive nodes and clinical node palpability are the most important prognostic factors. The standard treatment is wide local excision with nodal dissection. The only adjuvant therapy approved by the FDA at present is high-dose interferon (IFN)-α_2b. For patients with clinically positive lymph nodes, a diagnostic nodal biopsy (e.g., fine-needle biopsy) is recommended and, if positive, a therapeutic lymphadenectomy is performed. Traditionally, patients with satellitosis or in-transit metastases on an extremity have been candidates for treatment with isolated limb hyperthermic perfusion/infusion with chemotherapeutic agents such as melphalan.

Stage IV melanoma has a very poor prognosis, with patients demonstrating a 5-year survival below 5%. The presence of BRAF mutations has transformed the systemic management of stage IV melanoma. Until 2011, only two treatments, dacarbazine and high-dose interleukin-2 (HD-IL-2), were FDA-approved for the treatment of stage IV melanoma. HD-IL-2 requires administration as an in-patient and can carry significant toxicity risks including capillary leak syndrome, renal failure, and neurologic toxicity. Given its toxicity profile, only a very limited number of patients are appropriate candidates for this treatment.

It has become increasingly evident that melanoma is a molecularly heterogeneous disease. Recently, sequencing of components of the MAPK pathway in a panel of cancer cell lines identified activating mutations in the downstream BRAF protein in 50–60% of melanomas. Over 90% of the mutations in BRAF occur at position 600, with the most common being a V600E mutation.

Vemurafenib is a potent inhibitor of V600E mutated BRAF. A randomized phase III study of first-line systemic therapy in patients with stage IV melanoma demonstrated a statistically significant overall survival benefit following vemurafenib treatment when compared to dacarbazine treatment. However, vemurafenib’s median progression-free survival is only 5.3 months. As such, elucidating resistance mechanisms is extremely important. Inhibition of the MAPK pathway downstream of BRAF by using the MEK inhibitor trametinib also confers a significant overall survival benefit relative to treatment with chemotherapy in patients with V600-mutated melanoma.

Approximately 15–30% of patients treated with BRAF inhibitors develop cutaneous squamous cell carcinomas. These carcinomas are believed to result from paradoxical activation of the MAPK pathway in cells containing both wild-type BRAF and active RAS.

A limitation of BRAF inhibition is its duration of benefit. Immunotherapies offer the potential for longer lasting benefit as demonstrated by the small subset of patients who develop durable responses to HD-IL-2. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is an immunomodulatory protein which downregulates T-cell activity. Inhibition of CTLA-4 using the monoclonal antibody ipilimumab has antitumor activity in melanoma. Treatment of stage IV melanoma patients with ipilimumab has an overall survival benefit when compared to treatment with a peptide vaccine. An overall survival benefit is also seen following treatment with the combination of ipilimumab and dacarbazine when compared to treatment with single agent dacarbazine.

Both vemurafenib and ipilimumab were FDA-approved in 2011 for the treatment of stage IV melanoma. There is a pressing need to develop strategies to improve the durability of molecularly targeted therapy and the response rate of immunomodulatory therapy. Combination approaches including dual therapy with ipilimumab and vemurafenib are under active investigation. Therapies that combine BRAF and MEK inhibition are being investigated with the theory that dual pathway inhibition will delay the onset of resistance and decrease the incidence of cutaneous toxicity. Targeting the subset of melanomas that contain a mutation in KIT as opposed to BRAF with oral inhibitors of KIT generates responses in patients, but also with limited durability.

Antibody-mediated inhibition of immunomodulatory proteins other than CTLA-4 may prove efficacious. Targeting either the programmed death 1 protein (PD-1) or its ligand PD-L1 produced durable responses in a subset of patients with melanoma. PD-1 is an inhibitory receptor on T cells whose immunosuppressive ligand PD-L1 is expressed on many melanomas. The interaction of PD-1 to its ligand is particularly important in regulating immune activity in the tumor microenvironment. Strategies that combine CTLA-4 and PD-1 blockade are currently in clinical trial. Learning how to optimally modulate the immune system and to durably apply targeted therapies can potentially change the landscape of melanoma therapy with the goal that treatment becomes less palliative and more curative in its intent.

Specific investigations

First-line therapies

Surgical excision	B
Selective lymphadenectomy	C
Elective lymphadenectomy	C

Second-line therapies

Pegylated interferon alfa-2b	A
Paclitaxel and carboplatin	D
Imiquimod	E
Interleukin-2	B
Isolated limb perfusion	E
Bcl-2 antisense and dacarbazine	A
Dacarbazine	A
Dacarbazine	A
Vemurafenib	A
Trametinib	B
Imatinib	B

Third-line therapies

Radiation therapy	B
Mohs micrographic surgery	B