From a patient's perspective, toxicities of interferons fall into two groups: 1) an acute complex of fever, chills, malaise, and arthralgias and 2) chronic constitutional effects of fatigue, anorexia, weight loss, depression, impaired cognitive function, and diminished sexual interest or function [1]. The acute toxicities primarily occur on the first or second day of administration and are rarely difficult to manage thereafter; the chronic side effects are more troublesome and may become dose limiting. Myelosuppression, although common, usually occurs as a nadir plateau, reverses within a few days of stopping therapy, and is rarely of clinical importance. Hepatotoxicity may be a serious side effect, but it occurs infrequently. These toxicities almost certainly represent an extension of the cellular effects of the more than 30 genes whose expression is modulated by interferons [2]. However, little attention has been paid to the pathophysiologic mechanisms underlying the toxicities or, more important for quality of life and cost-effectiveness, to which therapeutic interventions might alleviate the chronic side effects.

Fatigue related to interferon may arise from endocrinologic, neurologic, or muscular causes. Abnormal thyroid function, usually presenting as hypothyroidism but occasionally as hyperthyroidism, may occur after several months in as many as 20% of patients receiving interferons [3, 4]. This abnormal function is often associated with thyroid autoantibodies. Interferons may modulate the function of the hypothalamic-pituitary-thyroid, hypothalamic-adrenal, or hypothalamic-gonadal axes either directly or through induction of other cytokines (such as interleukin-1b, interleukin-1ra, tumor necrosis factor-, or interleukin-6). Weight loss may result from anorexia and may also be directly induced by hypothalamic dysfunction. In one study [5], direct intracerebroventricular administration of interferon- in picogram or nanogram amounts caused early satiety in rats; these findings support patient reports of early satiety. Interferon- also excites glucose-sensitive neurons in the hypothalamus that are involved in the control of feeding [6]. This effect was potentiated by other cytokines, such as interleukin-1b [5].

Although depression induced by interferon may be nothing more than minor feelings of sadness, some patients receiving interferons meet the psychiatric criteria for major depression. These criteria include diminished appetite, weight loss, insomnia or hypersomnia, agitation or mental retardation, fatigue, and diminished ability to concentrate. In one study [7], patients with chronic myelogenous leukemia who had been receiving interferon- for a mean of 26 months had abnormal mood and cognitive function compared with patients with chronic myelogenous leukemia who had not received interferon-. More than half of the treated patients had elevated scores on the depression subscale of the Minnesota Multiphasic Personality Inventory. Twice as many patients treated as those not treated performed poorly on a test of verbal memory. Interferon- recipients also did significantly worse than controls in assessments of executive function, motor speed, and dexterity.

Increases in dose and duration of treatment can increase the number of symptoms of toxicity [8, 9]. This is unfortunate because increased dose and duration of treatment are also important for optimal therapeutic effectiveness. In one study [10], for example, a lower dose of interferon- was less effective than a higher dose in reducing the number of patients who became negative for antibody to hepatitis B virus and the number of patients who lost hepatitis B e antigen. For oncologic applications, dose and sustained administration will probably also prove to be more beneficial in inducing remission and improving survival.

Specific interventions to alleviate the chronic side effects should be developed. A recent meeting, co-sponsored by the University of Maryland Cancer Center and the National Cancer Institute, considered the underlying pathophysiology of the side effects of interferon in an effort to develop rational approaches to managing these side effects. Megestrol acetate has improved the appetite and increased the body weight of patients with cancer or human immunodeficiency virus infection. One study suggested that megestrol acetate may have a role in alleviating symptoms of anorexia or weight loss in patients receiving interferons [11]. Other nutritional manipulations, such as growth hormone (which causes an increase in lean body mass in patients with the acquired immunodeficiency syndrome [12]) or omega-3 fatty acids (which decrease the production, activity, and anorectic effects of interferon-ß [13]), merit evaluation. Opioid antagonists may be able to reverse changes in neurophysiologic and neuroendocrine function caused by interferon- [14]. Because interferons may decrease serotonin levels [15], trials of antidepressant selective serotonin reuptake inhibitors are being initiated.

In this issue, Kattan and colleagues [16] compare the cost-effectiveness of interferon- with that of conventional chemotherapy for chronic myelogenous leukemia. The marginal cost-effectiveness was $26 500 per year of life saved. This Figure is similar to those of other accepted therapies, such as renal dialysis and adjuvant chemotherapy for breast cancer. The model was particularly sensitive to changes in the cost of interferon; thus, any reduction in the cost would result in even greater cost-effectiveness. The cost-effectiveness of effective alternative treatments for chronic myelogenous leukemia, such as allogeneic bone marrow transplantation, must be separately compared with the cost-effectiveness of interferons. An analysis of the use of interferons for chronic active hepatitis resulting from hepatitis B virus infection also concluded that interferon- was cost-effective [17].

When difficulty tolerating the drug is the issue, it becomes important to measure quality of life in addition to cost-effectiveness. Kattan and colleagues used a physician panel to judge quality of life during interferon therapy compared with that during other therapies. Although this approach has shortcomings when compared with patient-based evaluation, the panel judged that for any side effect that was less severe than severe angina, interferon therapy was associated with better outcomes in terms of quality-adjusted years of life saved than was chemotherapy. The first licensure of a biological agent to prevent microscopic occult cancer after surgery in high-risk patients resulted from a study in patients who were treated for 1 year after resection of primary melanoma [18]. A Q-TWIST (quality time without symptom and toxicity) analysis of that trial [19] showed an advantage for interferons compared with conventional management (in that study, no treatment).

Interferons are proving to be effective therapy for an increasing number of defined indications, even when cost-effectiveness and effects on quality of life are considered. However, more such analyses are needed for other diseases that respond to interferons. The toxicities of interferons are not trivial, but, in most patients, the chronic side effects reverse within a few weeks of discontinuation of therapy. Effective interventions to reduce the number of these chronic side effects would further improve quality of life for patients receiving interferons. Controlled clinical research studies to identify such interventions should be more actively pursued.