Interferon alpha therapy is associated with substantial side effects in relation to the neurologic, cutaneous, musculoskeletal, gastrointestinal, cardiovascular, renal, hepatic, and hematologic systems, which may affect the ability to deliver the full course of therapy. In addition to the controversies regarding dose-response, to our knowledge there is no international consensus regarding and little rigorous trial data to support the optimal duration of interferon therapy, which has ranged from 1 month (using intravenous high-dose IFN) to as long as 5 years.
Interferon side effects mainly reflected in IFN toxicities to numerous organ systems. Toxicities can be associated with the individual IFN dose regimen (eg, flu-like symptoms), in which tachyphylaxis describes the phenomenon of improved tolerance with daily versus more intermittent administration. Other side effects are associated with cumulative IFN dose or with duration of therapy (eg, anorexia and weight loss). Some side effects are completely independent of dose and duration. Although interferon side effects also may be characterized as acute or chronic, some may appear to some extent throughout treatment (Fig. 1).
Figure 1. Interferon side effects
Flu-like symptoms (fever, chills, headache, myalgia, nausea, vomiting) are acute; they last approximately 1to 12 hours after dose administration, and tolerance develops during continued therapy. However, tolerance may be lost with a break in therapy for more than 1 day. Premedication with acetaminophen, antiemetics, or nonsteroidal anti-inflammatory drugs, as well as adequate hydration during therapy, can reduce the intensity of these symptoms. IFN administration at bedtime also may be helpful.
Mild elevations in hepatic enzymes without clinical symptoms are common in patients who are treated with IFNα2b. In addition to interferon administration, other potential causes for elevated hepatic enzymes during the course of interferon therapy include alcohol consumption or underlying disease, such as hepatitis B or C. These coexisting conditions should be ruled out before ascribing hepatotoxicity to IFN. Although treatment with HDI is not precluded in the presence of hepatitis B or C, an increase in the degree of hepatic function surveillance, including liver biopsy and involvement of the hepatology service in management of such cases, is recommended. In addition, patients should avoid other hepatotoxic agents, including anesthetics, statins, and large quantities of alcohol, during interferon treatment. Acetaminophen should be used judiciously, and patients should be cautioned regarding the risks of exceeding recommended dosages.
Fatigue is a common side effect of interferon and is reported in 70% to 100% of patients. Causes of fatigue may be endocrine, neuropsychiatric, autoimmune, or cytokine dysregulation. Individuals most prone to fatigue include those who have a compromised performance status, those who are receiving higher doses of IFN, and those who are older. Patient performance should be assessed before initiating treatment and periodically during therapy.
Patients who are treated with interferon may complain of anorexia, weight loss, or early satiety. Patients should be encouraged to eat small, frequent meals; to use high-protein supplements; and to take multivitamins. The patient and family should be counseled regarding realistic expectations with regard to meal preparation, meal times, and changes in eating habits and food preferences.
The most frequently reported IFNα-induced neuropsychiatric side effects are depression and irritability; however, an acute confusional state, anhedonia, fatigue, apathy, weight loss, sleep disturbances, tremor, sexual dysfunction, impaired memory, manic symptoms, cognitive dysfunction, and suicidal ideation also are reported.
In 1 series of 44 patients who were treated with IFNs of all types, the most common cardiac events were cardiac arrythmias (primarily in patients with previous disturbances of cardiac pace), dilated cardiomyopathy, and ischemic heart disease. Treatment of cardiotoxicity consists of discontinuing IFN and employing standard approaches to the management of cardiac failure. Hypothyroidism can be an underlying cause of cardiac dysfunction, and can have a variety of effects on the heart, such as ventricular dilation, pericardial effusion, and poor contractility.
It has been demonstrated that IFN-α precipitates or exacerbates autoimmune endocrine diseases, particularly thyroid disorders. Induction of autoimmunity may itself play a role in IFN efficacy. The ability of IFN to induce autoimmunity reportedly was an independent predictive biomarker of relapse-free survival and overall survival in a Phase II study conducted in patients with high-risk melanoma (E2696).
Erectile dysfunction and a decrease in libido have been described in some men who received IFN. Numerous medications are available for the treatment of erectile dysfunction and may be helpful.
Retinopathy (retinal hemorrhages, cotton wool spots) or optic neuropathy have been reported in <1% of patients who are treated with interferon. Retinopathy generally is mild and does not cause visual loss in most patients. Patients with diabetes and hypertension are at increased risk for developing ocular toxicity. Ocular toxicity may occur at any time during treatment; a correlation between dose or duration of interferon therapy and ocular toxicity has not been well established. Although, in most patients, visual acuity returns to normal when IFN is discontinued, visual loss can be permanent. Of concern, in 1 series of 7 patients who developed retinopathy while undergoing treatment with IFN, 6 patients had received concurrent paroxetine. In another series of 20 patients who received paroxetine for depression prophylaxis, 3 patients experienced retinal hemorrhage.