Advances in Adjuvant Therapy for the Treatment of High-risk Melanoma

Oncology & Hematology Review 2013;9(2):132–7

Abstract:

The global incidence of melanoma is increasing, and the prognosis for patients remains poor. High-dose interferon-alpha (HD-IFN-a) and pegylated IFN are the only US Food and Drug Administration (FDA)-approved agents for adjuvant therapy for high-risk melanoma, and an improvement in relapse-free survival (RFS) has been observed consistently across nearly all published studies and meta-analyses. Some studies and meta-analyses have also supported an overall survival (OS) benefit. However, despite a number of adjuvant studies, controversy remains regarding the role of this treatment. As the benefits in OS are modest with IFN treatment, there is therefore a need for new therapeutic targets, new drugs, and optimum patient selection. Current research is investigating new adjuvant agents, either individually or in combination, which may advance the standard of care beyond HD-IFN. Additionally, identifying biomarkers of patients with greater likelihood of response may allow patient-specific therapeutic approaches. Following the recent FDA approval of ipilimumab, vemurafenib, dabrafenib, and trametenib for metastatic melanoma, ongoing adjuvant trials are now underway. Acknowledgements: Editorial assistance was provided by Katrina Mountfort at Touch Medical Media.
Keywords: Adjuvant therapy, interferon-alpha, ipilimumab, melanoma, vemurafenib
Disclosure: Kenneth F Grossman, MD, PhD, has received honoraria from Prometheus for travel and funding trainees to attend meetings. He has completed uncompensated advisory work for Roche/Genentech. Shelley Christiansen, MD, has no conflicts of interest to declare.
Received: October 24, 2013 Accepted November 25, 2013 Citation Oncology & Hematology Review 2013;9(2):132–7
Correspondence: Kenneth F Grossmann, MD, PhD, 2000 Circle of Hope Drive, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84106, US, E: kenneth.grossmann@hci.utah.edu
Support: The publication of this article was supported by Prometheus. The views and opinions expressed are those of the authors and not necessarily those of Prometheus.

Melanoma represents 4% of all malignant tumors of the skin yet is responsible for 80% of deaths from skin cancer; it was estimated that 9,180 people would die of melanoma in 2012.1 The disease disproportionately targets young people: from 2005 to 2009 the age-adjusted incidence rate of melanoma in the US was 21.0 per 100,000 men and women per year, 58.5% of whom were below the age of 64.1 The number of new cases of melanoma in the US has been increasing for the last 30 years: between 1985 and 2009, the incidence of melanoma in the US has more than doubled.1 Treatment of early-stage melanoma by surgery can be curative, but patients with locally advanced disease have a high risk for recurrence and death. Localized melanoma has a 98.2% 5-year survival rate; however, if the cancer has metastasized the 5-year survival rate is 15.1%.1 The American Joint Committee on Cancer (AJCC) classification is the most widely accepted staging system for melanoma and has been recently updated.2 Despite considerable research, the treatment of advanced disease remains challenging. Historically, the alkylating agent, dacarbazine (DTIC), has been the standard therapy for patients with metastatic melanoma. High-dose interleukin-2 (HD IL-2) has been shown to achieve durable long-term complete responses in a small proportion of patients.3 In 2011, the US Food and Drug Administration (FDA) granted approval for ipilimumab (an anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] human monoclonal antibody) and vemurafenib (an inhibitor of proto-oncogene B-Raf [BRAF] kinase); in 2013, dabrafenib and trametinib were approved for the management of stage IV disease harboring BRAF mutations. The current treatment for melanoma with lymph node involvement, but without distant metastasis, is surgical excision and lymph node dissection. However, the risk for recurrence of melanoma after surgery is reported to be approximately 60% for stage IIB patients and 75% for stage III patients.4 The probability of recurrence is defined as low, intermediate, or high risk depending on the thickness of the primary tumor, the presence of ulceration or mitoses in the primary tumor, and the presence of nodal or in-transit or satellite metastases around the primary lesion.5,6 Adjuvant therapy is offered after surgical treatment has removed all detectable disease and is given with the intent of reducing relapse risk due to occult disease. Adjuvant therapy should be considered for patients whose risk for recurrence exceeds 30%, i.e. patients with either stage IIB melanoma with a primary thickness greater than 4 mm or greater than 2 mm with ulceration or stage III melanoma.4 For patients with stage I–II disease, sentinel node mapping, a procedure that identifies micro-metastatic disease in the regional lymph nodes with greater precision than an elective lymph node dissection, may be used to select patients for adjuvant therapy.7 This article will discuss the use of IFN-a in the adjuvant setting and will outline other evolving options including vaccines, CTLA-4 blockade, chemotherapy, and radiotherapy.
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Keywords: Adjuvant therapy, interferon-alpha, ipilimumab, melanoma, vemurafenib