Update on Adjuvant Interferon Therapy for High-Risk Melanoma
Update on Adjuvant Interferon Therapy for High-Risk Melanoma
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 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