ABSTRACT: Melanoma is almost 100% curable when diagnosed early, but when metastatic to distant organs, it is associated with a poor survival. The interferons have shown the most promise in the treatment of melanoma and interferon-alpha has been the most extensively studied. In recent trials, interferon alfa-2b (Intron A) administered at maximally tolerated doses for 1 year produced improvements in both relapse-free and overall survival. The importance and impact of the IV induction component of high-dose interferon regimens is currently being evaluated in an Intergroup randomized trial. A trial of the GMK vaccine vs high-dose interferon in patients with high-risk melanoma closed early when an interim analysis detected a markedly inferior response in the GMK arm compared to the high-dose interferon arm. The use of surgical staging will help to better define prognostic groups and support ongoing efforts for more effective adjuvant therapy. [ONCOLOGY 16:1177-1197, 2002]
Of all the cancers that lend themselves to adjuvant therapy, melanoma is unique for several reasons. It is almost 100% curable if diagnosed at an early stage, yet almost invariably lethal when metastatic to distant organs. It is visible on the skin surface and thereby lends itself to early detection, but is remarkably insidious in its propensity to spread to lymphatic and distant blood-borne sites. More importantly, there is an abundance of well-defined prognostic factors that, when correctly applied, enable rational decisions regarding adjuvant therapy based on the potential for recurrence and development of metastases.
Among the many prognostic factors for localized cutaneous melanoma that correlate with relapse and mortality, two are the most reproducible and accurate: the thickness of the lesion measured in millimeters (Breslow classification scheme) and the presence or absence of ulceration. The latter is defined as the absence of an intact epidermis overlying the melanoma on microscopic examination. Indeed, thickness of the lesion distinguishes stage I disease from stage II disease in the 1997 American Joint Committee on Cancer (AJCC) staging system, and the presence or absence of ulceration has been incorporated into the revised AJCC system adopted in 2002.
Spread to the regional lymph nodes implies stage III disease, and once this has occurred, the number of metastatic lymph nodes and the degree of involvement (whether they are microscopically or macroscopically involved), become the most important prognostic factors. Accurate assignment of stage at diagnosis is now possible with sentinel lymph node biopsy, which allows detection of microscopic involvement of regional lymph nodes and a directed elective lymphadenectomy.
Based on these prognostic factors, the AJCC staging system for melanoma divides the disease into four stages. Stages I and II comprise tumors localized to the skin without regional lymph node involvement. Stage III disease includes microscopic or macroscopic evidence of spread to the regional lymph nodes. Metastasis beyond the regional lymph node basin or to distant organs constitutes stage IV disease. Not surprisingly, 5- and 10-year survival rates decrease progressively with increasing stage.
Patients with stage I melanoma (T1-2, N0, M0) have an excellent long-term survival prognosis, achieving a cure rate of more than 85% with surgical treatment alone. Postsurgical relapse rates for stage II melanoma are somewhat higher, ranging from 20% to 30% for stage IIA patients and 40% to 55% for stage IIB patients at 3 to 5 years. Patients with stage III melanoma and regional lymph node metastasis are surgically curable in 20% to 40% of cases but have 5-year relapse rates of 60% to 80%.
Notably, the 1997 AJCC system does not differentiate between microscopic involvement in a single lymph node and multiple clinically involved lymph nodes. Recent analysis of several databases by the Melanoma Staging Committee of the AJCC has led to revisions of this system to enable differentiation between patients with a single, positive microscopic lymph node (estimated 5-year relapse-free survival: 69% ± 4%) and clinically involved lymph-node metastases (estimated 5-year relapse-free survival: 25%-50%). The dismal prognosis of individuals with stage IV melanoma has remained relatively unchanged over the past 2 decades, with most series reporting median survivals of 6 to 9 months.
The principle underlying the use of adjuvant therapy in melanoma patients is the presumption that micrometastatic disease, which is more susceptible to early treatment, may exist as a source of future relapse. Patients targeted for adjuvant therapy, therefore, have been those considered at high risk for relapse, including patients with thick primary lesions (T4, AJCC stage IIB) and those with disease metastatic to the regional lymph nodes (AJCC stage III). In the new AJCC staging system, the "high-risk" population has been redefined to distinguish between patients with low-tumor-burden stage III disease (microscopic involvement of a single node) and those with high-tumor-burden stage III disease (multiple involved nodes, clinically palpable nodes). The imperfections of the 1997 system partially explain some of the difficulties that arose in the interpretation of clinical trials conducted recently by cooperative groups in the United States and Europe.
Strategies incorporating chemotherapeutic agents that have been successful in other malignancies have not proven to be effective as adjuvant therapy for melanoma. Experimental evidence demonstrating the importance of the immune system in this disease and the confirmed activity of immunotherapeutic approaches for stage IV melanoma have led to exploration of immunotherapy agents such as the interferons and the interleukins in the adjuvant setting. Of the various agents tested, the one that has most successfully delayed relapse and improved survival is interferon-alpha. This update reviews the current status of this agent in the adjuvant treatment of melanoma, with an emphasis on data from recently completed and ongoing randomized trials.
The interferons are a family of proteins with pleiotropic effects that include immunomodulation and antiproliferative activity. Several types of interferons have been described; they can be broadly divided into type I and type II.
Type I interferons include interferon-alpha and -beta. They are structurally related, produced by a variety of cell types, and induced in response to exposure to viruses or nucleic acids. Although only one gene codes for interferon-beta, interferon-alpha is encoded by at least 14 closely related genes and several pseudogenes on chromosome 9.
Type II interferon (interferon gamma-1b [Actimmune]) is produced mainly by T lymphocytes and natural killer (NK) cells, bears little homology to type I interferon, and is encoded by genes located on chromosome 12. The two types of interferon also differ in their receptor-ligand interactions: Interferon-alpha and -beta share a common receptor distinct from the one that binds interferon-gamma, inducing an intracellular signal transduction cascade that differs from that of the latter.
Since their identification in 1956 by Isaacs and Lindemann, the interferons have been investigated in various neoplastic diseases. In early studies, impure preparations of interferon-alpha were found to have antitumor activity in diseases ranging from non-Hodgkin’s lymphoma and multiple myeloma to sarcoma. Recombinant DNA technology has allowed the production of unlimited quantities of pure interferons, facilitating their systematic evaluation in various malignant and nonmalignant diseases.
Mechanism of Action
Relevant to their activity in melanoma, the immunoregulatory functions of interferons have been well documented, both in vitro and in vivo. These immunomodulatory effects include modulation of the expression of class I and II major histocompatibility complex (MHC) antigens, non-MHC-restricted and MHC-restricted effector cells (NK cells, T cells, monocytes), and dendritic cells. Through interaction with these and other cells, the interferons may play a central role in antitumor applications against tumor-restricted antigens. The growth inhibitory effects of interferons on melanoma cells in vitro are well established and occur through binding to specific cell-surface receptors.
In human melanoma, interferon-alpha has shown the most promise and has been the most extensively evaluated biological agent for adjuvant and advanced-disease applications, alone and in combinations. Three types of interferon-alpha are commercially available: interferon alfa-2a (Roferon-A), -2b (Intron A), and -2c (which is not marketed in the United States); each differs minimally in amino-acid sequence.
It is useful to divide considerations for the adjuvant use of interferon-alpha in melanoma into two settings: high-risk disease, traditionally defined as AJCC stage IIB or III, and intermediate-risk, defined as AJCC stage IIA or IIB. The overlap in the categories of stage II disease is a result of clinical vs pathologic staging of the regional lymph nodes as practiced in different geographic and professional communities. Low-risk patients (AJCC stage I) have not been subjected to adjuvant therapy trials due to their excellent long-term prognosis.
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