Risk Reductions of Recurrence and Mortality in Melanoma Patients Using IFN-α

Introduction

Melanoma is the fastest growing malignancy in the United States in terms of incidence. In the year 2015, it is estimated that 73,870 men and women will be diagnosed with cutaneous melanoma in the United States and that 9940 will die as a result of this disease ( ).

The American Joint Committee on Cancer (AJCC) staging system divides melanoma patients into four stages that correspond to patient prognosis ( ). Stages I and II constitute melanoma that is limited to the skin and where the risk is defined by the depth of the tumor, the presence or absence of surface ulceration, and the mitotic rate. High mitotic rate (at least 1 mitosis/mm ² ) correlates with declining survival and has replaced the Clark level of invasion as a complementary criterion to ulceration for differentiating T1a versus T1b primary tumor in the most recent AJCC update ( ). Every millimeter increase in tumor depth (Breslow’s tumor thickness) corresponds to a significant decline in survival; the 10-year survival rate drops from 92% for T1 tumors (thickness ≤1 mm) to 50% with T4 melanoma (thickness >4 mm). Ulceration of the primary tumor leads to proportionately lower survival than nonulcerated melanoma of equivalent T category but is similar to patients with a nonulcerated melanoma of the subsequent T category. For instance, survival rates with T3b and T4a are approximately similar (68% and 71%, respectively), whereas it falls to 53% in the T4b population ( ).

AJCC Stage III constitutes melanoma spread to regional lymph nodes and/or the presence of intralymphatic (satellite or in-transit) metastasis. Nodal subclassifications N1a (micrometastasis) and N1b (macrometastasis) are also different by prognosis and prognosis also worsens with the increase in the number of lymph nodes involved ( ). In-transit lymphatic metastases without and with metastatic lymph nodes are classified as N2c and N3, respectively ( ). Stage IV consists of distant metastatic spread of melanoma. The number and location of metastasis and lactate dehydrogenase blood levels impact patient prognosis ( ).

Studies of interferon-α (IFN-α) adjuvant therapy in melanoma have primarily targeted patients with AJCC stages IIB, IIC, and III, while one study (E2696) also enrolled subjects with surgically resected stage IV. These patients carry an estimated risk of recurrence that exceeds 30% (ranging from 30% chance of recurrence for IIB to 89% chance of recurrence for IIIC) ( ). Approximately, this population of patients is 3 times the size of the population with metastatic disease ( ).

Interferon-α: Biology and Clinical Applications in Cancer

IFN-α belongs to the type I IFN family, also including -β, -δ, -ε, -κ, -τ, and -ω subtypes ( ). It was long ago discovered that type I IFN is secreted in response to viral, bacterial, or tumor cell stimuli by leukocytes, and later it was demonstrated that a specific population of CD4 ⁺ CD11c¯ (plasmacytoid Dendritic cell precursors (pDCs)) is the predominant producer ( ).

IFN-α has undergone extensive clinical evaluation over the past four decades. Clinically used recombinant formulations of IFN-α exist in three isoforms (α2a, α2b, α2c) and it has regulatory approval for the adjuvant treatment of high-risk melanoma (IFN-α2b, also in its pegylated form), as systemic treatment for metastatic renal cell carcinoma (α2a, α2b in combination with bevacizumab), AIDS-related Kaposi’s sarcoma (α2b), follicular lymphoma (α2b), hairy cell leukemia (α2a, α2b), chronic myelogenous leukemia (PH chromosome+, α2a), condyloma acuminata (α2b), cervical intraepithelial neoplasms (α2b) ( ).

The interferon molecule anticancer activity is thought to be mediated through an immunomodulatory effect primarily, and less so in terms of a directly cytotoxic or antiangiogenic effect ( ). IFN-α has significant immunomodulatory effects where it polarizes the immune response toward Th1, enhances cytotoxicity and survival of NK cells, induces the generation and survival of both cytotoxic T lymphocytes and memory CD8 ⁺ T cells, positively regulates antibody production, promotes dendritic cell maturation, chemotaxis and CD8 ⁺ priming against tumor antigens ( ). Additionally, IFN-α exhibits direct antitumor activity by upregulation of MHC I surface molecules, promotes caspase-dependent apoptosis in certain types of cancer, and has antiangiogenic effects on tumor vasculature ( ).

A study of IFN-α in the melanoma neoadjuvant setting has shown a significant impact of IFN-α on Signal Transducer and Activator of Transcription (STAT) signaling ( ). An influx of dendritic cells (DCs) and T lymphocytes into the tumor tissue was shown to result from neoadjuvant IFN-α ( ). IFN-α was found to downregulate STAT3 expression in tumor cells and to stimulate the induction of STAT1 that correlated with a reversal in T cell signaling defects ( ).

Studies of IFN-α in Stage IV Inoperable Melanoma

Phase I and II studies that tested IFN-α as systemic therapy for advanced inoperable Stage IV melanoma reported response rates of about 16%. Responses were seen as late as 6 months from the initiation of IFN-α therapy. One-third of the responses were reported as durable, and included complete responses ( ). IFN-α was also tested as part of the biochemotherapy (BCT) regimen (consisting of IFN-α, interleukin-2, dacarbazine, cisplatin, vinblastine) and has been used, as an off-label systemic therapy, for stage IV inoperable melanoma, both as monotherapy and as part of BCT ( ).

Adjuvant IFN-α Trials in Melanoma

Trials testing IFN-α as systemic adjuvant therapy for high risk surgically resected melanoma have evaluated several different regimens. These regimens have varied by the duration of therapy, the route of administration, the dose level and the formulation. The impetus to study IFN-α in the adjuvant setting was the evidence of clinical activity in the more advanced metastatic setting. The series of adjuvant IFN-α trials completed and reported over the years have been pooled in a number of meta-analyses, the largest of which has most recently supported its adjuvant therapeutic efficacy in terms of both disease-free survival and, to a lower extent, overall survival (OS) ( ).