Interferon-α is possibly the most controversial adjuvant therapy for any solid tumor, and multiple trials involving varying doses, routes, schedules, and formulations of interferon-α have increased the confusion. Clinicians are left in a quandary, because high-dose interferon-α-2b (HDI) remains the only FDA-approved adjuvant therapy for high-risk melanoma. Of the three prospective randomized trials involving high-dose interferon-α-2b, all show a significant improvement in disease-free survival and two show a significant improvement in overall survival. Despite this strong evidence, data from studies involving alternate doses, concerns regarding cost and toxicity, and the promise of future therapies have led opponents of interferon to overlook these results. Based on the available clinical evidence, however, high-dose interferon should be offered as standard care for patients with high-risk, resected melanoma. Informed patients who have elected to forego interferon and patients with lower risk lesions can be offered participation in clinical trials with a no-treatment control arm.
Michael S. Sabel and Vernon K. Sondak
Joyce Y. Wong and Vernon K. Sondak
Radical wide excision with appropriate margins based on depth of tumor invasion has been the standard adopted in NCCN and national clinical practice guidelines in oncology based on randomized controlled trial data. When carefully scrutinized, however, questions remain unanswered about what constitute appropriate margins in many frequently encountered clinical situations. In addition to the single characteristic of tumor depth, factors such as primary tumor location, histologic classification, and even specific patient characteristics may all contribute to risk for local recurrence, and therefore should potentially be considered in margin recommendations. This article addresses current uncertainty surrounding optimal margin status in primary cutaneous melanoma.
Jonathan S. Zager, Jane L. Messina, L. Frank Glass and Vernon K. Sondak
Many unanswered questions remain about what constitutes appropriate guidelines for treatment of Merkel cell carcinoma (MCC). In this review, we address current uncertainty surrounding optimal management of MCC. These areas of uncertainty include early recognition features; clinical and histopathologic prognostic factors; optimum margins of excision of the primary tumor; indications for and value of surgical staging of the clinically negative regional nodes; optimum management of the patient with pathologically positive regional nodes; and indications for and value of radiation to the primary and regional nodes. Through identifying and elaborating on these areas of uncertainty, the authors hope to foster additional research and ultimately improve the evidence base for future iterations of the NCCN Clinical Practice Guidelines in Oncology in this rare but increasingly encountered cutaneous malignancy. The intent, however, is not to exhaustively identify all areas of controversy, but rather to highlight clinically relevant questions that further studies could address to improve the standard of care for MCC.
Damon Reed, Ragini Kudchadkar, Jonathan S. Zager, Vernon K. Sondak and Jane L. Messina
The rising incidence of melanoma in children has brought increased attention to the clinical and pathologic diagnosis of pigmented lesions in the pediatric age group. Although melanoma in infancy and early childhood is often associated with large congenital nevi, in older children and teenagers it is most often sporadic, occurring in patients with a low skin phototype and substantial sun exposure. The rarity of this potentially fatal disorder demands astute clinical attention and a high index of suspicion for atypical lesions in pediatric patients. The challenges include the difficult decision of whether to biopsy and an often equivocal pathologic diagnosis. These diagnostically challenging and equivocal lesions lead to a degree of uncertainty regarding additional workup, prognosis, potential therapy, and follow-up plans. Consultation with a specialty dermatopathologist can be very helpful, and advanced molecular diagnostic techniques may be used in selected circumstances. Although still controversial, good evidence exists to justify a role for sentinel lymph node biopsy. Patients with atypical melanocytic proliferations have a high rate of positive sentinel lymph nodes; however, their outcomes are clearly better than in similarly staged adults with conventional melanoma. With the multiple variables involved and the relative lack of prospectively derived evidence, clinical decision-making is challenging and patients and families may experience considerable stress. This article provides data and weighs the pros and cons of a rationale for decision-making in pediatric and young adult patients with diagnostically challenging melanocytic lesions.
Tobin Strom, Javier F. Torres-Roca, Akash Parekh, Arash O. Naghavi, Jimmy J. Caudell, Daniel E. Oliver, Jane L. Messina, Nikhil I. Khushalani, Jonathan S. Zager, Amod Sarnaik, James J. Mulé, Andy M. Trotti, Steven A. Eschrich, Vernon K. Sondak and Louis B. Harrison
Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board–approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30–60 Gy) in 27 fractions (range, 5–30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13–180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05–0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24–92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.