Key message: interferon alpha improves both disease-free survival and overall survival of people with high-risk cutaneous melanoma. Interferon is also valid as a reference standard for future trials of other new treatments.

Cutaneous melanoma is a type of skin cancer that’s on the rise in all Western countries and carries with it a poor chance of survival for those in whom the cancer has spread, with around 10% surviving longer than five years. For those whose cancer has not spread, their outlook after surgery is variable; between 40% and 90% are alive after five years. Interferon alpha is the only drug approved for adjuvant (additional) treatment of high-risk cutaneous melanoma after surgery, but not enough has been known about its benefits for it to be offered as a standard treatment. A new review from the Cochrane Skin Group has brought together evidence from randomised controlled trials (RCTs) assessing the effects of interferon alpha, as an adjuvant treatment, on disease-free survival and overall survival in high-risk patients. High-risk patients were defined as those in whom the cancer had spread to the lymph nodes or whose primary tumour was more than one millimeter thick. Eighteen trials with over 10,000 people were included, comparing interferon alpha with observation or other treatments.

What did they find?

• Adjuvant interferon was associated with significantly improved disease-free survival and overall survival

The numbers: Adjuvant interferon was associated with significantly improved disease-free survival (HR (hazard ratio) = 0.83; 95% CI (confidence interval) 0.78 to 0.87, P value < 0.00001) and overall survival (HR = 0.91; 95% CI 0.85 to 0.97; P value = 0.003).

• Whether some treatment features, such as dose and length of time taking it, have an impact of its effectiveness, or whether subgroups of patients (such as those with our without lymph node involvement) benefit differently, remains unknown
• Side-effects such as fever and tiredness were mostly not severe and went away when the treatment finished

How good was the evidence?

The reviewers judged the evidence to be of high quality, allowing for robust conclusions about the impact of interferon. They were able to perform meta-analyses (combining results) on 10, 345 people in 17 RCTs for disease-free survival and 9927 people from 15 RCTs for overall survival. There was generally low risk of bias in the studies.

Why is this review important?

Hywel Williams, Professor of Dermato-Epidemiology at the University of Nottingham and Co-ordinating Editor of the Cochrane Skin Group, comments:

“It was always unclear to me whether adjuvant therapy with agents like interferon alpha were really worthwhile for people diagnosed with melanoma at high risk of disseminated disease. I knew they could increase disease-free survival, but I was unclear whether they improved overall survival, and if so at what cost in terms of side effects. This review has illustrated to me that interferon alpha not only improves disease-free survival by about 17%, but also overall survival by about 9%. Not a huge benefit granted, but a benefit nevertheless. The studies were fairly similar and I have confidence in these estimates. The side effects of interferon alpha were not severe in the majority and seemed to disappear when treatment was completed. The review has provided important evidence to inform patient choices and has also established a reference standard that other new adjuvant agents can be measured against in future studies.”

This is an important review, then, for people with this life-threatening disease and the doctors treating them and also future trialists. More research is needed to establish which patients are most likely to benefit from this treatment.

Links:

Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V. Interferon alpha for the adjuvant treatment of cutaneous melanoma. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD008955. DOI: 10.1002/14651858.CD008955.pub2.

Cochrane summary http://summaries.cochrane.org/CD008955/interferon-for-the-treatment-of-melanoma-patients-after-surgical-removal-of-their-tumour