Interferon for melanoma
What is interferon?
The interferons are a family of biological proteins (cytokines) produced by a variety of cells. They have immunomodulatory and antiproliferative effects on tumour cells and can be broadly divided into type I (interferon-alpha and beta) and type II (interferon-gamma).
Three types of interferon-alpha are commercially available: interferon alfa-2a (Roferon®-A, Hoffmann-La Roche, New Jersey [NJ], USA), interferon alfa-2b (Intron A®; Schering-Plough Corporation, Madison NJ, USA), and peginterferon alfa-2b (Sylatron®; Schering-Plough Corporation, Madison NJ, USA); each differs minimally in their amino-acid sequence.
Both interferon alfa-2a and interferon alfa-2b are available in New Zealand for melanoma treatment; peginterferon alfa-2b was approved by the FDA in USA for the adjuvant treatment of melanoma in 2011, but is not available in New Zealand.
How interferon works
- The interferons are biologic response modifiers.
- They bind to specific cell-surface receptors and communicate between various cells.
- Interferon alfa interferes directly with the cancer cells' ability to divide, and indirectly by modifying the bodies’ immune response to the cancer cells.
- The immunomodulatory effects occur by modulation of the expression of class I and II major histocompatibility complex (MHC) antigens, non-MHC-restricted and MHC-restricted effector cells (Natural Killer cells, T lymphocyte cells, monocytes), and dendritic cells.
How is interferon administered?
Interferon alfa-2a (Roferon®-A)
- Interferon alpha-2a is indicated for the treatment of malignant melanoma (stage IIB, IIC, IIIA IIIB or IIIC) alone or in combination with dacarbazine and as an adjuvant after surgery.
- The drug is administered by subcutaneous injection (SC).
- Each pre-filled syringe (for single-dose, subcutaneous injection) contains 3, 6 or 9 MIU (million international units) interferon alfa-2a.
- Initial dosage of interferon alfa-2a is 18 M IU three times a week for 8–12 weeks.
- Maintenance dosage is 18 MIU three times a week for up to 24 months.
- Patients should be treated for a minimum of 8 weeks and preferably for 12 weeks before the physician decides to continue treatment in responding patients or to discontinue treatment in nonresponding patients.
- Interferon alfa-2a with dacarbazine (DTIC): 9–18 MIU of interferon alfa-2a should be given daily or three times a week. Concomitant treatment with dacarbazine should be given as a single IV infusion at 21 day intervals, starting at 200mg/m2 with dose increments up to 400 and 800 mg/m2 if tolerated.
- The use of interferon alfa-2a is not recommended in children, as its safety and effectiveness have not been established.
Interferon alfa-2b (Intron® A)
- Interferon alpha-2b is indicated for the treatment of malignant melanoma as an adjuvant to surgical treatment in patients with melanoma that are free of disease (post-surgery) but at high risk for systemic recurrence.
- The drug is administered within 56 days after surgery.
- Induction therapy: interferon alpha-2b is administered intravenously at a dose of 20 million IU/m2 daily for five days a week over a four-week period.
- Maintenance therapy: the recommended dose is 10 million IU/m2 administered subcutaneously three days a week (every other day) for 48 weeks.
- If severe adverse reactions occur, treatment should be temporarily discontinued, and treatment restarted at 50% of the previous dose.
- Interferon alpha-2b should be discontinued if intolerance persists.
Peg-interferon alfa-2b (Sylatron®)
- Pegylation of interferon involves conjugation with polyethylene glycol.
- This extends the serum half-life by reducing the rate of absorption, renal and cellular clearance, making once weekly injection possible.
- Peg-interferon alfa-2b is indicated for the adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.
- The recommended dose is 6 µg/kg/week subcutaneously for 8 doses, then 3 µg/kg/week subcutaneously for up to 5 years.
- Premedication with acetaminophen 500 to 1000 mg orally 30 minutes prior to the first dose of peg-interferon alfa-2b is recommended and as needed for subsequent doses to help reduce 'flu-like symptoms.
- Peg-interferon alfa-2b should be discontinued permanently for persistent or worsening symptoms of neuropsychiatric disorders.
- The drug should be withheld if the absolute neutrophil count is < 0.5x109/L and/or the platelet count is < 50 X 109/L, and dosing resumed at a reduced level when haematological toxicity has resolved.
- Treatment is contraindicated in patients with a history of anaphylaxis to peginterferon-alpha 2b or interferon-alpha 2b.
What are the side effects of treatment with interferon?
In clinical trials, the most common side effects (greater than or equal to 20%) in patients receiving interferons were:
- 'flu-like symptoms (fever, headache, tiredness, muscle or joint aches, chills or loss of appetite).
- feeling sad or depressed (Sylatron)
- redness, swelling, or itching around the injection site
- low white blood cell counts
- increased liver enzyme levels
Peg-interferon alfa-2b can cause serious side effects including worsening of pre-existing conditions such as:
- heart problems (fast heart rate, difficulty breathing and chest pain)
- decrease in vision/blurred vision
- severe or worsening liver problems (yellowing of skin and swelling of abdomen)
- thyroid problems (problems concentrating, feeling hot or cold at all times, loss of weight)
- memory changes and aggressive behaviour towards others
Peginterferon alfa-2b should be discontinued permanently in patients with persistently severe or worsening signs or symptoms of depression, psychosis, or encephalopathy.
Drug interactions with interferon
- When administering Sylatron® at a dose of 1 µg/kg/week at the same time as medications metabolized by the hepatic cytochrome P-450 (CYP) enzymes (CYP2C9 or CYP2D6), the therapeutic effect of these drugs may be altered.
- The effects of pegylated interferon alfa-2b on the pharmacokinetics of drugs metabolized by cytochrome P-450 enzymes have not been studied at the higher clinical doses (3 µg/kg/week and 6 µg/kg/week).
- Roferon-A has been reported to reduce the clearance of theophylline.
- The neurotoxic, haematotoxic or cardiotoxic effects of concurrently administered medicines may be increased by all interferons.
- Results from a controlled clinical study demonstrated no significant effect of bevacizumab on the pharmacokinetics of interferon alfa-2a.
- Caution should be exercised when administering interferon alfa-2b in combination with other potentially myelosuppressive agents.
- A synergistic adverse effect on the white blood cell count may occur when interferon alfa-2b is administered concomitantly with zidovudine. Patients receiving the two agents concomitantly have had a dose-dependent higher incidence of neutropenia than when zidovudine is administered alone.
Use of interferon in special patient populations
Use in pregnancy (pregnancy category B3)
- Interferon has been shown to have abortifacient effects in rhesus monkeys.
- There are no adequate and well controlled studies in pregnant women.
- Intron A® or Sylatron® should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
Use in nursing mothers
- It is not known whether interferon or its metabolites are excreted in human milk.
- Because many drugs are excreted in human milk, mothers should discontinue nursing prior to using interferon .
- The safety and effectiveness of interferon have not been established in children.
- Patients with decompensated liver disease, autoimmune hepatitis or a history of autoimmune liver disease should not be treated with interferon.
- The mean area under the concentration-time curve (AUC) following a single dose of peginterferon alfa-2b at 1 µg/kg increased by 1.3-, 1.7- and 1.9-fold in subjects with mild (creatinine clearance 50–79 mL/min), moderate (creatinine clearance 30–50 mL/min) and severe (creatinine clearance 10–29 mL/min) renal impairment, respectively.
- The frequency of monitoring renal toxicity in patients with moderate and severe renal impairment should be increased when treating patients with peginterferon alfa-2b.
- The effect of varying degrees of renal impairment on the pharmacokinetics of peginterferon alfa-2b at the recommended doses of 3 µg/kg or 6 µg/kg in patients with melanoma has not been studied.
- Clinical studies of peginterferon alfa2-b did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.