Background
Interferon alpha is the only agent approved for the postoperative adjuvant treatment of high‐risk cutaneous melanoma. However, the survival advantage associated with this treatment is unclear, especially in terms of overall survival. Thus, adjuvant interferon is not universally considered a gold standard treatment by all oncologists.
Objectives
To assess the disease‐free survival and overall survival effects of interferon alpha as adjuvant treatment for people with high‐risk cutaneous melanoma.
Search methods
We searched the following databases up to August 2012: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, issue 8), MEDLINE (from 2005), EMBASE (from 2010), AMED (from 1985), and LILACS (from 1982). We also searched trials databases in 2011, and proceedings of the ASCO annual meeting from 2000 to 2011. We checked the reference lists of selected articles for further references to relevant trials.
Selection criteria
We included only randomised controlled trials (RCTs) comparing interferon alpha to observation (or any other treatment) for the postoperative (adjuvant) treatment of patients with high‐risk skin melanoma, that is, people with regional lymph node metastasis (American Joint Committee on Cancer (AJCC) TNM (tumour, lymph node, metastasis) stage III) undergoing radical lymph node dissection, or people without nodal disease but with primary tumour thickness greater than 1 mm (AJCC TNM stage II).
Data collection and analysis
Two authors extracted data, and a third author independently verified the extracted data. The main outcome measure was the hazard ratio (HR), which is the ratio of the risk of the event occurring in the treatment arm (adjuvant interferon) compared to the control arm (no adjuvant interferon). The survival data were either entered directly into Review Manager (RevMan) or extrapolated from Kaplan‐Meier plots and then entered into RevMan. Based on the presence of between‐study heterogeneity, we applied a fixed‐effect or random‐effects model for calculating the pooled estimates of treatment efficacy.
Main results
Eighteen RCTs enrolling a total of 10,499 participants were eligible for the review. The results from 17 of 18 of these RCTs, published between 1995 and 2011, were suitable for meta‐analysis and allowed us to quantify the therapeutic efficacy of interferon in terms of disease‐free survival (17 trials) and overall survival (15 trials). 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). We detected no significant between‐study heterogeneity (disease‐free survival: I² statistic = 16%, Q‐test P value = 0.27; overall survival: I² statistic = 6%; Q‐test P value = 0.38).
Considering that the 5‐year overall survival rate for TNM stage II–III cutaneous melanoma is 60%, the number needed to treat (NNT) is 35 participants (95% CI = 21 to 108 participants) in order to prevent 1 death. The results of subgroup analysis failed to answer the question of whether some treatment features (i.e. dosage, duration) might have an impact on interferon efficacy or whether some participant subgroups (i.e. with or without lymph node positivity) might benefit differently from interferon adjuvant treatment.
Grade 3 and 4 toxicity was observed in a minority of participants: In some trials, no‐one had fever or fatigue of Grade 3 severity, but in other trials, up to 8% had fever and up to 23% had fatigue of Grade 3 severity. Less than 1% of participants had fever and fatigue of Grade 4 severity. Although it impaired quality of life, toxicity disappeared after treatment discontinuation.
Authors' conclusions
The results of this meta‐analysis support the therapeutic efficacy of adjuvant interferon alpha for the treatment of people with high‐risk (AJCC TNM stage II‐III) cutaneous melanoma in terms of both disease‐free survival and, though to a lower extent, overall survival. Interferon is also valid as a reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of this participant population. Further investigation is required to select people who are most likely to benefit from this treatment.
Author(s)
Simone Mocellin, Marko B Lens, Sandro Pasquali, Pierluigi Pilati, Vanna Chiarion Sileni
Plain language summary
Interferon for the treatment of melanoma patients after surgical removal of their tumour
Cutaneous melanoma is one of the deadliest types of skin cancer, and its incidence is rising in all Western countries. Furthermore, melanoma is one of the solid tumours most resistant to treatment with chemotherapy, which means that the outlook for people whose cancer has spread through their body (distant metastatic disease) is dismal, with only 10% of these patients surviving longer than 5 years.
After surgical removal of the primary tumour and in the absence of distant metastatic disease, people with melanoma have variable prognosis: In fact, between 40% to 90% of these patients are alive after 5 years. Therefore, adjuvant (i.e. postoperative) therapy has been proposed to reduce the risk of death in patients with high‐risk melanoma who have more aggressive tumours that are identified according to pathological features, such as the primary tumour thickness and regional lymph node status (disease stage).
The only compound that has shown some positive therapeutic effects in this patient group is interferon alpha, which is a protein produced by human macrophages (one type of white blood cell) and is known for its antiviral and antitumour activities.
In this review, we gathered evidence from 18 randomised controlled trials, enrolling more than 10,000 participants, testing the hypothesis that interferon treatment can improve the survival of people with melanoma at high risk of spreading after surgical removal of the tumour.
Whereas not all single studies demonstrated a survival benefit for patients treated with interferon, combining the available evidence, we found that the use of postoperative interferon improves the survival of those with high‐risk melanoma. On average, the toxicity associated with interferon administration (such as fever and fatigue) is limited; moreover, it is reversible when the treatment is stopped. Since interferon alpha is the only approved drug after surgery for those with high‐risk melanoma, efforts to identify those who might benefit most from this treatment are very important in order to avoid unnecessary toxicity for those who would not benefit from interferon alpha treatment. Combination of interferon with novel drugs is another field of ongoing research to improve the life expectancy of people with high‐risk melanoma.
Author(s)
Simone Mocellin, Marko B Lens, Sandro Pasquali, Pierluigi Pilati, Vanna Chiarion Sileni
Authors' conclusions
Implications for practice
Our findings support the efficacy of adjuvant interferon alpha (interferon) for the treatment of participants with high‐risk (AJCC TNM stage II‐III) cutaneous melanoma in terms of both disease‐free survival and, to a lesser extent, overall survival. High‐grade toxicity was observed in a minority of participants, who reported impairment in their quality of life. Nevertheless, participants reported relief from symptoms and improvement in quality of life after treatment discontinuation.
Until better selection methods or more effective therapies are available, the findings of the present meta‐analysis lend support to the use of interferon in the routine clinical setting to provide patients with the best chance of survival.
Implications for research
The results reported above cannot be fully satisfying in terms of antimelanoma efficacy. In fact, considering a 5‐year OS rate of 60% for participants with TNM stage II–III cutaneous melanoma (Balch 2009), the number needed to treat (NNT) is approximately 35 participants (95% CI 21 to 108 participants). Therefore, much more effort is clearly warranted to improve these results. This might be achieved in three main ways.
A) By identifying participants who actually need adjuvant treatment:
B) By elucidating the molecular mechanisms underlying melanoma responsiveness to interferon:
C) By developing new treatments that are more effective than interferon against minimal residual disease.
Until better selection methods or more effective therapies are available, the findings of the present meta‐analysis lend support to the use of interferon in the routine clinical setting to provide patients with the best chance of survival. Moreover, we must remember that other well‐established adjuvant treatments, such as those routinely administered to people with breast, colorectal, and ovarian carcinomas, are associated with risk reductions very similar to those found in this meta‐analysis for those with high‐risk melanoma treated with interferon (Ascierto 2008). Therefore, the need for better therapeutic strategies is an urgent issue for virtually all tumour types.
Finally, the findings of this meta‐analysis support interferon alpha as the reference treatment in RCTs investigating new therapeutic agents for the adjuvant treatment of high‐risk melanoma participants. One such trial, comparing interferon and ipilimumab in AJCC TNM stage III‐IV melanoma participants after surgery (an immunostimulating agent acting by inhibiting CTLA‐4), has been designed by ECOG and is currently ongoing (ECOG E1609, clinicaltrial.gov identifier: NCT01274338).