Much on the Horizon in Surgical and Locoregional Treatment of Melanoma

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Emerging concepts in the treatment of melanoma include new definitions for stage I/II and stage III disease, new surgical paradigms that incorporate systemic neoadjuvant therapy for advanced disease, and locoregional treatment with intralesional therapies that have both local and distant effects, said presenters at the 2015 World Cutaneous Malignancies Congress.

Surgical Treatment

Evolving paradigms in surgical treatment of melanoma were summarized by Merrick Ross, MD, Professor of Surgical Oncology, MD Anderson Cancer Center, Houston, TX. The new melanoma landscape has been sculpted by sentinel lymph node (SLN) biopsy, which has established a new stage I/II patient population as well as a new stage III population.

Regional lymph nodes are the most common site of first relapse after a wide excision of primary melanoma. When that happens, there is a 15% to 50% chance for in-basin failure after dissection, and a >50% chance for distant relapse.

The concept of selective lymphadenectomy has since emerged, with the use of lymphoscintigraphy to identify lymphatic drainage patterns.

SLN biopsy is performed for nodal staging and to improve disease outcome for node-positive patients through the prevention of the development of clinical node development. Wide excision plus SLN biopsy with immediate complete lymph node dissection (CLND) of positive nodes was shown to outperform wide excision alone in terms of melanoma-specific survival (20% improvement in 10-year survival) in node-positive patients with primary melanoma ≥1 mm. CLND after a positive SLN remains the standard of care, said Ross.

In patients with stage III melanoma, survival rates are heterogeneous based on absence or presence of ulceration, the number of nodal micrometastases, and the number of nodal macrometastases. Standard of care for advanced stage III melanoma is up-front surgery, selective use of adjuvant nodal basin irradiation, adjuvant interferon, or enrollment into a clinical trial.

For the treatment of stage IV disease, there have been 6 new drug approvals in the past 2 years, but each has some disadvantages. Although responses are robust with BRAF inhibition, these responses are not durable. The response rate with ipilimumab is lower than with combination checkpoint blockade, but the latter approach has significant toxicity. Surgery for stage IV patients is well tolerated and has a 100% response rate. “So it’s not crazy to still consider selectively, for patients with stage IV disease, surgery as an up-front option,” he said.

An emerging strategy in stage III and IV melanoma is a neoadjuvant approach in which patients receive preoperative systemic therapy, based on BRAF mutation status, followed by surgical resection and postoperative adjuvant therapy for stable disease. With locally progressive disease without distant sites, surgery would still be indicated, but with systemic progression after neoadjuvant treatment, patients would not be candidates for surgery. “It gives you an insight into marker for response,” Ross said. “Another emerging strategy with some of these novel therapies is that we’re being asked to resect resistant sites of disease.”

Neoadjuvant clinical trials are in progress and include studies of dabrafenib/trametinib, ipilimumab/nivolumab, talimogene laherparepvec (T-VEC), and pembrolizumab/pegylated interferon.

Mohs Surgery

To date, there is no evidence that a wide (5 cm) excision improves overall survival or melanoma-specific survival compared with a 1-cm margin when margins are determined by visual inspection. It is on this basis that Mohs micrographic surgeons successfully treat metastatic melanoma with unconventionally narrow margins, said David Brodland, MD.

The primary goal of excision is the complete removal of the tumor. Most guidelines of melanoma treatment categorically list 1- to 2-cm margins as the standard, but “day of surgery” histologic tumor-free margin confirmation should be done, argued Brodland, Assistant Professor, Departments of Dermatology, Plastic Surgery, and Otolaryngology, University of Pittsburgh, PA. “Mohs advances the concept of intraoperative 100% margin examination…it’s better to look.”

The evidence base for the effectiveness of Mohs surgery is extensive, he said, with 5-year survival and metastasis rates at least equivalent to wide local excision and marginal recurrence not any more likely (J Am Acad Dermatol. 1997;37:422-429). Most malignant melanomas were successfully excised with 6-mm margins.

Mohs micrographic surgery was found to be especially effective for malignant melanoma of the head, neck, hands, and feet. The overall marginal recurrence rate when performed at these sites was 1.2% (0.2% in primary tumors of the head and neck), decreasing the need for future surgery, decreasing morbidity and cost, and decreasing the risk of metastasis from a persistent primary tumor. Margins can be accurately assessed using frozen section histology, he indicated.

One criticism of Mohs is that it is incompatible with SLN biopsy, but there is no evidence that tumor excision prior to SLN biopsy adversely affects the ability to perform one.

Intralesional Therapy

Melanoma is a systemic disease, and intralesional therapies in development have systemic effects, said Sanjiv S. Agarwala, MD, Chief, Oncology and Hematology, St. Luke’s Cancer Center, Bethlehem, PA.

The goals of intralesional therapy are durable tumor shrinkage, symptom control and palliation, a systemic effect, delay or prevention of systemic therapy, and neoadjuvant potential.

Several intralesional agents are in development, including T-VEC, PV-10 (Rose Bengal), plasmid interleukin-12 electroporation (IL-12 EP), and coxsackievirus A21 (CVA21), among others.

T-VEC is a herpes simplex virus 1–derived oncolytic immunotherapy that has both a local and distant effect. It selectively replicates in the tumor to cause rupture of the tumor cells and also causes a tumor-specific immune response. In the OPTiM phase 3 study (J Clin Oncol. 2015;doi:10.1200/JCO.2014.58.3377) comparing T-VEC with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF), the durable response rate was significantly higher with T-VEC versus GM-CSF (16.3% vs 2.1%; P <.0001). In T-VEC responders, the complete response rate was 41%. There was also a trend toward a survival benefit after median follow-up of 44.4 months in patients treated with T-VEC.

PV-10 is a nonpyrogenic solution of Rose Bengal disodium (10% RB) for intralesional injection. It accumulates in the lysosomes of cancer cells and causes necrosis. A phase 2 trial of PV-10 in patients with stage III and IV melanoma has been completed, with a response rate of 51% in target lesions. “Perhaps with some surprise…we’re seeing a bystander effect; a significant [33%] response rate in noninjected lesions,” said Agarwala. “Like other intralesional therapies, the one recurring theme is that the toxicity is very marginal. That allows us to treat a much larger patient population.”

A phase 3 trial with PV-10 in patients with BRAF wild-type locally advanced melanoma is ongoing.

Plasmid-encoded DNA IL-12 EP has been studied in a phase 2 clinical trial of patients with advanced melanoma (J Clin Oncol. 2014;32[suppl]. Abstract 9025). Interim analysis of 28 patients showed an objective response rate of 32% and a complete response rate of 11% at 24 weeks. The response rate in untreated lesions was 59%.

As with other intralesional therapies, intralesional CVA21 causes viral replication and lysis of cancer cells and also has an immune effect. In the CALM phase 2 study of patients with unresectable stage IIIC-IV M1c melanoma (J Clin Oncol. 2015;33[suppl]. Abstract 9030), the overall response rate was 28.1%, and 19.3% had a durable response (≥6 months). Of evaluable patients, 38.6% had an immune-related progression-free survival (irPFS) at 6 months, and the median irPFS was 4.2 months.

“The future of intralesional therapy probably lies in combinations, or as monotherapy in patients who cannot receive systemic therapy,” said Agarwala. The effect of intralesional and systemic therapy in combination may be synergistic, he said, as with T-VEC in combination with ipilimumab and T-VEC in combination with pembrolizumab. T-VEC neoadjuvant treatment with surgery is also being compared with surgery alone in a phase 2 trial of patients with surgically resectable stage IIB/C/IV M1a melanoma.

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