Interferon for melanoma

Author: Anoma Ranaweera, Medical Writer, Auckland, New Zealand. Chief Editor: Dr Amanda Oakley, Dermatologist, Hamilton, New Zealand, December 2015.


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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).

In melanoma, interferon-alpha has shown most promise and has been the most extensively evaluated for advanced disease (including metastatic melanoma), alone and in combinations.

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.

Link to key clinical-trial evidence about interferons ...

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
  • nausea/vomiting
  • 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)
  • diabetes
  • 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 .

Paediatric use

  • The safety and effectiveness of interferon have not been established in children.

Hepatic impairment

  • Patients with decompensated liver disease, autoimmune hepatitis or a history of autoimmune liver disease should not be treated with interferon.

Renal impairment

  • 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.

Geriatric use

  • 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.
New Zealand approved datasheets are the official source of information for these prescription medicines, including approved uses and risk information. Check the individual New Zealand datasheet on the Medsafe website.

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References

  • Thalanayar PM, Agarwala SS, Tarhini AA. Melanoma adjuvant therapy. Chin Clin Oncol 2014; 3(3): 26. Journal
  • Di Trolio R, Simeone E, Di Lorenzo G, Buonerba C, Ascierto PA. The use of interferon in melanoma patients: a systematic review. Cytokine Growth Factor Rev 2015; 26: 203–12. PubMed
  • Ascierto PA, Chiarion-Sileni V, Muggiano A, et al. Interferon alpha for the adjuvant treatment of melanoma: review of international literature and practical recommendations from an expert panel on the use of interferon. Chemother 2014; 26: 193–201. PubMed

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Text: Miiskin