Cochrane Database of Systematic Reviews

Interferon alpha for the adjuvant treatment of cutaneous

melanoma (Review)

Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V

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.

www.cochranelibrary.com

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 6. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
Analysis 1.1. Comparison 1 Interferon alpha versus any other comparator, Outcome 1 Disease-free survival (DFS). . 61
Analysis 1.2. Comparison 1 Interferon alpha versus any other comparator, Outcome 2 Overall Survival (OS). . . . 62
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 74
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) i

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Interferon alpha for the adjuvant treatment of cutaneous

melanoma

Simone Mocellin1,2 , Marko B Lens3 , Sandro Pasquali4 , Pierluigi Pilati4 , Vanna Chiarion Sileni5
1 Istituto Oncologico Veneto, IOV-IRCCS, Padova, Italy. 2 Dept. Surgery Oncology and Gastroenterology, University of Padova, Padova,

Italy. 3 Genetic Epidemiology Unit, King’s College london, London, UK. 4 Meta-Analysis Unit, Department of Surgery, Oncology and
Gastroenterology, University of Padova, Padova, Italy. 5 Medical Oncology Unit 2, Veneto Region Oncology Research Institute, Padova,
Italy
Contact address: Simone Mocellin, Dept. Surgery Oncology and Gastroenterology, University of Padova, Via Giustiniani 2, Padova,
Veneto, 35128, Italy. simone.mocellin@unipd.it. mocellins@hotmail.com.
Editorial group: Cochrane Skin Group.
Publication status and date: Stable (no update expected for reasons given in ’What’s new’), published in Issue 11, 2015.
Review content assessed as up-to-date: 22 August 2012.
Citation: 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.

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT
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.
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 1
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
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.

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.

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 2

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Interferon alpha compared with treatment other than interferon (including observation) for the adjuvant treatment of melanoma

Patient or population: high-risk melanoma participants

Settings: adjuvant
Intervention: interferon alpha
Comparison: observation, treatments other than interferon, or both

Outcomes Illustrative comparative risks* (95% CI) Relative effect Number of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)

Assumed risk Corresponding risk

Observation or treat- Interferon alpha

ment

First recurrence 50/100 44/100 HR 0.83 (0.78 to 0.87) 10,345 (17 studies) High-quality Further research may pro-
vide information regarding
patient selection and inter-
feron schedule

Death 40/100 37/100 HR 0.91(0.85 to 0.97) 9927 (15 studies) High-quality Further research may pro-
vide information regarding
patient selection and inter-
feron schedule

*Assumed risk: For disease-free survival outcome: 5-year disease recurrence rate = 50%; for overall survival outcome: 5-year death rate = 40% (in patients with TNM stage II-III). The
corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI)
CI: Confidence interval; HR: Hazard ratio

GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate
Very low quality: We are very uncertain about the estimate
3
BACKGROUND
The management of people with lymph node metastases from cu-
taneous melanoma is one of the most challenging issues for surgi-
cal and medical oncologists. In fact, the therapeutic role of sentinel
node biopsy, radical lymph node dissection, and adjuvant ther-
apies has never been clearly proven (Australian Cancer Network
2008; Thompson 2009).
After surgery, the only approved medical adjuvant therapy for
people with lymph node metastases is interferon (IFN) alpha
(Kirkwood 1996). After the first trial reporting an overall sur-
vival benefit (Kirkwood 1996), the FDA (the United States Food
and Drug Administration) and the EMEA (European Medicines
Agency) approved high-dose interferon for the adjuvant treat-
ment of high-risk melanoma patients (i.e. TNM stage IIb-IIIC)
(Eggermont 2009). On the basis of this randomised controlled
trial (RCT), the standard regimen is currently one month of high-
dose intravenous interferon, followed by one year of low-dose IFN.
Following the RCT published by Kirkwood and Colleagues in
1996, many trials have been conducted to compare interferon
versus observation, or different interferon schedules and dosages
(Ascierto 2008). The results appear to confirm a benefit in terms
of disease-free survival, but the impact of adjuvant interferon on
overall survival is quite unclear (Kirkwood 2004; Lens 2002; Pirard
2004; Wheatley 2003). The results of an individual patient data
meta-analysis on this subject have been published in the form of
an abstract: They confirm longer disease-free survival for those
treated with IFN and, interestingly, pinpoint a small but significant
advantage in terms of overall survival (Wheatley 2007).
Based on the disease-free survival advantage, the small overall sur-
vival benefit, and the high toxicity, the role of interferon alpha
in melanoma remains debatable (Ascierto 2008; Bajetta 2008;
Eggermont 2008a; Janku 2010; Kirkwood 2009; Thirlwell 2008;
Verma 2006). Accordingly, because the overall survival benefit may
be small when weighed against possible toxicity, the international
guidelines do not routinely recommend interferon. However, in
those participants with metastatic regional lymph nodes who have
had a lymphadenectomy, some guidelines suggest its use may be
considered (Australian Cancer Network 2008; Dummer 2009;
Fecher 2009; Saiag 2007).
We present a glossary of terms used in this review in Table 1.
Description of the condition
Although melanoma is not the most common form of skin cancer,
it accounts for 80% of all skin cancer deaths (Jemal 2010; Lens
2004; Lui 2007; Tawbi 2007; Thompson 2005; Tsao 2004; Wang
2007). During the 20th century, the incidence of melanoma in
white populations rose faster than the incidence of any other solid
tumour, barring lung cancer (Ferlay 2010; Jemal 2010; Mocellin
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2011). Data from the United States indicates that in 2001, 47,700
new cases were recorded compared to 59,940 new cases in 2007.
Worldwide, 160,000 new cases and 41,000 deaths were reported
in 2002. In 2007, the American Cancer Society estimated that
the lifetime risk of melanoma is higher for men (1/49) than for
women (1/73), the death rate from melanoma reaching 8110 cases
in that same year (Wang 2007). These data clearly indicate that
cutaneous melanoma represents a growing public health problem.
Early diagnosis and surgical removal of the primary tumour still
represent the approach with the highest likelihood of cure for
participants with early stage melanoma (Mocellin 2011a; Sladden
2009). In this setting, sentinel node biopsy provides patients with a
significant benefit in terms of disease-free survival, and when there
is metastatic disease present in the regional lymph nodes, there
is a possible overall survival advantage (Morton 2006; Pasquali
2010a).
In people with advanced melanoma, resection is recommended for
selected cases with limited metastatic disease (Thompson 2005;
Tsao 2004). Anti-CTLA-4 monoclonal antibodies and inhibitors
of v-Raf murine sarcoma viral oncogene homologue B1 (BRAF)
recently gained the approval of drug agencies for AJCC stage IV
disseminated melanoma (Chapman 2011; Hodi 2010), a condi-
tion considered as one of the most resistant to conventional che-
motherapy (Crosby 2000; Gogas 2007; Lui 2007; Sasse 2007;
Tawbi 2007).
In those with high-risk melanoma, AJCC stage II (T2-4N0M0)
and AJCC stage III (TanyN+M0) disease, the 5-year overall sur-
vival rate varies between 30% and 70% (Balch 2009), and the only
agents currently approved for the treatment of these patients in
an adjuvant setting after radical surgery are interferon alpha and
pegylated interferon (Eggermont 2009; Garbe 2010; Kirkwood
2008).
Description of the intervention
Interferon alpha is a type I interferon mainly produced by
macrophages (Theofilopoulos 2005). The interferon cluster re-
gion of chromosome 9p22 encodes 13 different interferon genes:
Among them, the interferon-2 gene presents 3 polymorphic vari-
ants, known as interferon alpha 2a, interferon alpha 2b, and in-
terferon alpha 2c (Pestka 2007). Interferon alpha demonstrated
anticancer effects in both experimental models and in the clini-
cal setting, although its exact mechanism of action is still unclear
(Moschos 2007; Pasquali 2010). With regard to the treatment of
melanoma, only the proteins encoded by the interferon alpha 2a
and interferon alpha 2b genes, which differ in a single amino acid
at position 23 (lysine > arginine), have been tested as therapeutic
agents in the clinical setting, and human recombinant interferon
alpha 2b has been approved for the adjuvant treatment of this type
of skin cancer.
After apparently radical surgery of primary melanoma without
clinical evidence of distant metastases, the only approved medi-
4
cal adjuvant therapy for patients with high-risk melanoma is in-
terferon alpha (Kirkwood 2008). Based on the results from the
first trial reporting an overall survival benefit (Kirkwood 1996),
the US Food and Drug Administration (FDA) and the European
Medicines Agency approved the high-dose interferon (IFN) for
the adjuvant treatment of high-risk melanoma patients (i.e. AJCC
TNM stage IIB-IIIC) (Eggermont 2009). Recently, based on the
EORTC (European Organisation for Research and Treatment of
Cancer) trial 18991 (Eggermont 2008), the FDA approved pegy-
lated interferon. Currently, the standard regimen is one month of
high-dose intravenous IFN, followed by one year of low-dose in-
terferon. However, different schedules of interferon therapy have
also been tested (Lens 2006). There are four main approaches to
interferon therapy:
• high-dose interferon alpha administered for one month
(and followed by one year at a low dose),
• interferon alpha at an intermediate dose (tested for one or
two years),
• interferon alpha at a low dose (tested for one or three years),
or
• pegylated interferon.
High-dose interferon is burdened by the highest toxicity; however,
it is believed to be the most active regimen (Kirkwood 2008).
How the intervention might work
The best known physiological activity of interferons is their antivi-
ral function through their ability to inhibit the replication of dif-
ferent types of viruses, both by blocking the cell cycle machinery
and by stimulating the immune response. Interferon has also long
been recognised as an anticancer factor in both experimental and
clinical models (e.g. myeloid leukaemia, renal cell carcinoma, and
melanoma). However, the cellular and molecular mechanism un-
derlying this activity is still incompletely elucidated (Borden 2007;
Pasquali 2010). Interesting findings about the mechanism of ac-
tion of interferon in melanoma came from an observational study
in which interferon was administered as neoadjuvant treatment
in participants with clinically detectable lymph node metastases
(Moschos 2006). The subsequent radical lymph node dissection
allowed the investigators to study the effects of interferon on tu-
mour tissue and to examine immunologic and molecular biomark-
ers of tumour response. Interferon did not influence tumour cell
phenotype, proliferation rate, apoptosis, or angiogenesis. On the
other hand, a higher grade of tumour-infiltrating-mononuclear-
immune cell was observed in cases showing response to interferon
treatment. Therefore, the main anticancer effect of interferon is
currently believed to be linked to its immunostimulatory effects.
Why it is important to do this review
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Several randomised studies have been designed and conducted on
the use of interferon alpha as an adjuvant treatment for melanoma
(Cascinelli 2001; Eggermont 2008; Garbe 2008; Kirkwood 2004).
While the disease-free survival benefit for interferon treatment was
consistent across the trials, a meaningful overall survival benefit for
interferon therapy has been reported in some studies only (Garbe
2008; Kirkwood 1996). According to 2 meta-analyses published
more than 6 years ago on the results of 12 (Wheatley 2003) and
9 (Pirard 2004) randomised controlled trials, respectively, inter-
feron alpha appears to provide a statistically significant disease-
free survival advantage (mainly over observation) in participants
with high-risk cutaneous melanoma, whereas no impact on overall
survival was demonstrated. Since then, 2 other large randomised
controlled trials have been published that compared interferon and
observation. These enrolled 1700 participants, but the findings
have been conflicting in terms of overall survival benefit (1 trial
is positive: Garbe 2008, and the other one showed no differences:
Eggermont 2008).
With the aim of summarising the evidence on interferon, we car-
ried out a meta-analysis that compared interferon treatment versus
any other comparator than interferon in participants with high-
risk cutaneous melanoma (Mocellin 2010). Our findings con-
firmed the disease-free survival benefit reported by the previous
meta-analyses, and supported the significant 3% overall survival
advantage reported by the individual patient data meta-analysis of
Wheatley (Wheatley 2007). These meta-analyses did not include
results for at least two more trials (the Nordic Trial and the Sunbelt
Melanoma Trial), which are currently only available in abstract
form (Hansson 2011; McMasters 2008).
The most recent meta-analyses on interferon as adjuvant treatment
for melanoma have not investigated adverse events and quality
of life (Mocellin 2010; Wheatley 2007). Even if these topics are
relevant in oncology, these end points are not suitable for a meta-
analysis. In fact, almost all trials compare interferon to observation.
Interferon arms are intrinsically associated with lower quality of
life and presence of adverse events when compared to control arms;
thus, quality of life and adverse events data are hardly reported in
terms of summary data suitable for meta-analysis.
Therefore, we have performed this systematic review and meta-
analysed the available evidence in order to determine the true
benefit of interferon in the adjuvant treatment of melanoma.
OBJECTIVES
To assess the disease-free survival and overall survival effects of
interferon alpha as adjuvant treatment for people with high-risk
cutaneous melanoma.
We have not addressed adverse events and quality of life, even if
they represent a crucial issue in interferon alpha treatment, in this
5
systematic review, as virtually all trials have compared interferon
treatment with observation (i.e. no treatment).
METHODS
Criteria for considering studies for this review
Types of studies
We considered as eligible all randomised controlled trials that com-
pared interferon alpha with observation (or any regimen other than
interferon alpha) for the adjuvant treatment of skin melanoma.
Types of participants
We included people with high-risk skin melanoma, that is, those
with regional lymph node metastasis undergoing radical lymph
node dissection (AJCC stage III), or people without nodal disease
but with primary tumour thickness greater than 1 mm (AJCC
stage II).
Types of interventions
We included adjuvant (i.e. postoperative) interferon (experimental
arm) versus observation or any treatment other than interferon
(control arm).
Types of outcome measures
The main outcome measure was the hazard ratio (HR), defined as
the ratio between the risk of event (disease recurrence or death) in
the treatment arm (adjuvant interferon) and the same risk in the
control arm (no adjuvant interferon).
Moreover, for overall survival data, we calculated the number
needed to treat (NNT), defined as the number of participants to
be treated with IFN to avoid one event (death).
Primary outcomes
The primary outcomes considered were disease-free survival and
overall survival. The survival time was calculated from the date of
randomisation.
Search methods for identification of studies
We aimed to identify all relevant randomised controlled trials re-
gardless of language, publication status (published, unpublished,
in press, or in progress), or publication format (abstract, meeting
presentation, full-text article).
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Electronic searches
We searched the following databases up to 22 August 2012:
• the Cochrane Skin Group Specialised Register using the
following terms: melanoma* and (interferon* or interferon*);
• the Cochrane Central Register of Controlled Trials
(CENTRAL) 2012, issue 8, in The Cochrane Library using the
search strategy in Appendix 1;
• MEDLINE via OVID (from 2005) using the strategy in
Appendix 2;
• EMBASE via OVID (from 2010) using the strategy in
Appendix 3;
• AMED via OVID (Allied and Complementary Medicine,
from 1985) using the strategy in Appendix 4;
• LILACS (Latin American and Caribbean Health Science
Information database, from 1982) using the strategy in
Appendix 5; and
• ASCO (American Society of Clinical Oncology) Annual
Meeting Abstracts 2000 to 2011.
The UK and US Cochrane Centres have ongoing projects to sys-
tematically search MEDLINE and EMBASE for reports of trials
that are then included in the Cochrane Central Register of Con-
trolled Trials. Searching has currently been completed in MED-
LINE to 2004 and in EMBASE to 2009. Further searches of these
two databases were undertaken for this review by the Cochrane
Skin Group to cover the years not searched by the UK and US
Cochrane Centres for CENTRAL.
Trials registers
We searched the following trials registers using the terms
“melanoma” and “interferon” during the second half of 2011:
• The metaRegister of Controlled Trials (www.controlled-
trials.com).
• The US National Institutes of Health Ongoing Trials
Register (www.clinicaltrials.gov).
• The Australian and New Zealand Clinical Trials Registry (
www.anzctr.org.au).
• The World Health Organization International Clinical
Trials Registry platform (www.who.int/trialsearch).
Searching other resources
Reference lists
We checked the bibliographies of selected studies for further ref-
erences to relevant trials.
Data collection and analysis
We performed meta-analysis following the Cochrane Handbook for
Systematic Reviews of Interventions (Higgins 2011) and PRISMA
6
(Preferred Reporting Items for Systematic Reviews and Meta-Anal-
yses) guidelines (Moher 2009). We applied standard meta-analysis
methods (Sutton 2000) to evaluate the summary effect of postop-
erative interferon on disease-free and overall survival.
Selection of studies
We assessed eligibility of the retrieved articles by title and abstract
(SP and SM). If this information was insufficient for eligibility
assessment, we reviewed the full article.
Data extraction and management
Two authors extracted data (SP and ML), and a third author inde-
pendently verified the extracted data (SM). After all eligible stud-
ies had been identified, two authors independently performed a
quality evaluation of the heterogeneity between studies, randomi-
sation, blinding, and follow-up, as well as data extraction (SM and
SP). The authors achieved consensus on all results considered for
the final analysis.
The following data were retrieved (if reported): demographics,
study design, eligibility criteria, randomisation method, allocation
method, disease stage at enrolment, type of interferon alpha, in-
terferon alpha dosage, treatment duration, number of participants
enrolled, number of participants randomised, number evaluated
for data analyses, cross-over allowance and percentage, intention-
to-treat versus per-protocol findings, follow-up period, disease-
free survival, overall survival, and loss to follow up.
Assessment of risk of bias in included studies
We assessed risk of bias according to The Cochrane Collaboration
checklist (Higgins 2011):
(a) the method of generation of the randomisation sequence;
(b) the method of allocation concealment;
(c) the blinding of participants, clinicians, and outcome assessors;
(d) the presence of incomplete outcome data; and
(e) selective outcome reporting.
This information was recorded in a ’Risk of bias’ table, which is
part of the ’Characteristics of included studies’ table for each study.
Measures of treatment effect
The main outcome measure was the hazard ratio (HR), defined
as the ratio between the risk of event in the treatment arm (ad-
juvant interferon) and the same risk in the control arm (no ad-
juvant interferon). Hazard ratios were reported with their 95%
confidence intervals (CIs). Survival data (HR) were either entered
directly in RevMan or extrapolated from Kaplan-Meier plots us-
ing dedicated methods (Parmar 1998; Tierney 2007). Moreover,
for overall survival data, we calculated the number needed to treat
(NNT), defined as the number of participants to be treated with
IFN to avoid one event (death).
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Unit of analysis issues
For multiple-arm trials in which two (or more) interferon arms
were compared with the same control arm, we took within-study
correlation into consideration. As suggested by Borenstein and
colleagues (Borenstein 2009), we first computed a composite effect
size for the comparison of each interferon arm versus the control
arm. Next, we calculated the correlation factor (r) based on the
number of cases in each arm, which allowed us to compute the
variance (V) of the composite effect size according to the following
√ √
formula: V = 1/4 [(V1 + V2) + (2r* V1* V2)], where V1
and V2 are the variances of the original comparisons between
each treatment arm and the control arm. Using this variance, we
finally computed the standard error and then the 95% CI of the
composite effect.
Dealing with missing data
We contacted trial authors of included studies whenever data es-
sential for the meta-analysis were missing or unclear.
Assessment of heterogeneity
We assessed the consistency of results (effect sizes) among stud-
ies using the two standard heterogeneity tests: the Chi²-based
Cochran Q-test and the I² statistic (Higgins 2002). To be more
conservative, we considered that heterogeneity was statistically sig-
nificant when the Cochran Q-test P value was less than 0.1 (i.e.
the alpha level of significance for this test was set at 10%). In
addition, inconsistency across studies was considered low, moder-
ate, and high for I² statistic values lower than 25%, between 25%
and 50%, and greater than 50%, respectively. We considered het-
erogeneity significant either when the I² statistic was greater than
50%, the Q-test P value was smaller than 0.1, or both: In this
case, we applied the random-effects model to calculate the overall
effect (which assumes that studies do not share the same common
effect, and assigns a weight to each study taking into account both
within- and between-study variance), using the inverse variance
method of DerSimonian and Laird (DerSimonian 1986). In all
other cases, we applied the fixed-effect model.
Assessment of reporting biases
We used a funnel plot to detect the so-called “small study effect”.
In fact, publication and selection biases might burden small stud-
ies, which may show a lower methodological quality, possibly lead-
ing to a small effect in a meta-analysis, the smaller studies having
larger effects. Furthermore, between-trial heterogeneity, which is
observed in studies with a relatively small number of participants,
might lower the study effect (Sterne 2000). We formally investi-
gated funnel plot asymmetry with the Egger linear regression ap-
proach and the Begg rank correlation test: To be more conserva-
tive, we considered these tests statistically significant when the P
value was less than 0.1. We formally assessed the impact of a small
7
study effect bias on the summary effects by means of the ’trim &
fill’ method described by Duval and Tweedie (Duval 2000).
In order to assess the impact of “small” studies, we also performed
a sensitivity analysis (see Sensitivity analysis) by excluding these
trials. To this aim, we defined “small” as any study with a sample
size smaller than 400 based on the following parameters of an
ideal trial: A) minimum hazard ratio (HR) = 1.5; alpha level of
significance = 5%; statistical power = 80%; median survival in
controls = 60 months; accrual time = 36 months; follow-up time
= 48 months; randomisation ratio = 1:1.
Data synthesis
We used hazard ratios (HR) and 95% confidence intervals (CI)
to synthesise the summary effect of interferon in terms of both
disease-free survival and overall survival.
Moreover, based on the summary HR (calculated with the meta-
analysis) and the 5-year OS rate in the control population of par-
ticipants with AJCC stage II-III melanoma (roughly 60%), we cal-
culated the number needed to treat (NNT), which provides read-
ers with the number of participants to be treated with interferon
in order to avoid one event (i.e. death); to this aim, we followed
the method proposed by Altman (Altman 1999).
Subgroup analysis and investigation of heterogeneity
In order to investigate potential sources of heterogeneity, we used
subgroup analysis and metaregression (method of moments) for
the following factors: interferon dosage, treatment duration, type
of interferon alpha used, participants’ AJCC TNM stage (studies
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
have been conducted with the 5th and 6th edition of the TNM
staging manual), type of comparator, and year of publication.
Sensitivity analysis
We used the ’leave-one-out’ sensitivity analysis to systematically
ascertain the impact of individual randomised studies on the over-
all effect. We employed the exclusion of randomised studies for
specific reasons (e.g. differences in control arms or sample size) as
a further type of sensitivity analysis.
RESULTS
Description of studies
Since we systematically reported the details of the included and
excluded studies in the dedicated ’Characteristics of included
studies’ and ’Characteristics of excluded studies’ tables, here we
discuss some general aspects of the trials included in the meta-
analysis, as well as some peculiarities of specific RCTs.
Results of the search
The literature searches yielded 640 papers plus 4 papers from other
sources (we report the review’s flow diagram in Figure 1). Of these
644 references, we excluded 609 and considered the full text of
the remaining 35. We then excluded 17 and included 18.
8
 Figure 1. Study flow diagram

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 9

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Included studies
We included 18 RCTs, with a total of 10,499 participants. These
were published between 1995 and 2011. Table 2 summarises de-
sign, sample sizes, setting, participants, interventions, and out-
comes of eligible studies. All but one study (a phase II RCT) were
phase III RCTs.
Sample sizes ranged between 96 and 1388 participants.
Studies were conducted across Europe (mainly within centres be-
longing to the European Organisation for Research and Treatment
of Cancer (EORTC)), the United States (mainly within centres
belonging to the Eastern Cooperative Oncology Group (ECOG)),
and Australia.
Included studies investigated the impact of interferon alpha on
disease-free survival and overall survival of people with cutaneous
melanoma after surgery. All participants underwent radical surgery
for AJCC stage II (n = 810; 7.8%), AJCC stage III (n = 3512;
33.9%), or AJCC stages II-III (n = 6023; 58.3%) cutaneous
melanoma. Participants were both men and women, generally aged
18 to 70 years.
Out of 18 trials, 16 compared interferon to observation, while 2
trials (Kirkwood 2001; Kirkwood 2001a) compared interferon to
the GMK antimelanoma vaccine.
Interferon regimens varied in terms of dosage (high-dose (20 mega-
units (MU)/m²), intermediate-dose (10 MU/m²), and low-dose (1
to 3 MU/m²)), administration route (subcutaneously (s.c.), intra-
muscularly (i.m.), and intravenously (i.v.)), and duration of treat-
ment (4 months to 5 years), as detailed in the dedicated section:
’Characteristics of included studies’.
The two main causes of interruption to interferon treatment were
disease progression or toxic effects: In the latter case, rates of treat-
ment discontinuation (or dose reduction/delay) ranged from 0%
to 58% (median 15%).
In terms of surgery, all participants received primary tumour ex-
cision in both interferon and control arms. Radical lymph node
dissection was performed upon clinical and pathological evidence
of lymph node metastasis in all RCTs, except for the E1684
trial (Kirkwood 1996), in which the enrolled participants under-
went elective lymphadenectomy. Moreover, in trial EORTC18871
(Kleeberg 2004), the physician in charge performed elective lymph
node dissection at their own discretion. The spread to regional
lymph nodes was assessed mainly by means of physical exami-
nation (clinically evident metastatic disease) until the year 2000.
Thereafter, sentinel node biopsy for the detection of subclinical
metastatic disease was allowed by trial protocols. Many study de-
signs did not consider sentinel node biopsy, thus, precluding the
performance of subgroup meta-analysis based on the type of lymph
node positivity (i.e. macrometastasis (clinically palpable lymph
nodes) versus micrometastasis (i.e. revealed by pathological assess-
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
ment of the sentinel node biopsy)).
In one RCT (Kirkwood 2001a), the treatment arm regimen con-
sisted of interferon combined with GMK (a ganglioside-based an-
ticancer vaccine). Because GMK alone was used in the compari-
son treatment arm, this study allowed the evaluation of any thera-
peutic benefit of IFN treatment; thus, we included it in the meta-
analysis. In addition, we used the ’leave-one-out’ procedure as a
sensitivity analysis to determine whether this trial had any impact
on the overall effect estimated by the meta-analysis (see results in
Effects of interventions).
Since the findings from 2 trials, EORTC18871 and DKG80-1,
were reported in a single article as pooled results (and consequently
as pooled HRs) (Kleeberg 2004), we included these 2 trials as a
single study in the present meta-analysis.
Excluded studies
We reported the reasons for the exclusion of 17 studies in the
’Characteristics of excluded studies’ tables.
In one trial (Kokoschka 1990), although the authors mentioned
that participants were randomly selected to receive interferon ther-
apy, there was no mention of a corresponding control arm, and
it seemed that surgically treated melanoma participants who were
diagnosed at the time of the study were considered as a non-ran-
domised control group. In addition, participants with both AJCC
TNM stage II and stage III melanoma were enrolled without men-
tioning any randomisation, and the results were represented sepa-
rately as Kaplan-Meier curves for disease-free survival (DFS), with
no log-rank P values, for the two stages. Also, the authors of this
trial claimed that both stage I and stage II participants benefited
from IFN therapy, although no difference in DFS or OS was de-
tected between treatment and observation groups. All attempts to
contact principal investigators of this trial were unsuccessful.
For two RCTs, the results were partially excluded. In a three-arm
RCT (Garbe 2008), the observation group was compared with
both interferon alone and a combination of interferon and dacar-
bazine. In this case, we included only the comparison of IFN alone
versus observation. The IFN plus dacarbazine arm was designed
specifically to answer whether dacarbazine adds any therapeutic
advantage to IFN; thus, we did not include results from this arm in
the present meta-analysis. One RCT (McMasters 2008) included
two types of participants with AJCC TNM stage III disease: those
with positive sentinel lymph node based on standard pathological
evaluation and those classified as positive based on the results of
polymerase chain reaction (PCR) for melanoma-associated anti-
gens. Although sentinel lymph node ultra staging by means of
PCR methods is claimed to be associated with participant prog-
nosis (Mocellin 2007), we decided to exclude the PCR arm since
this was the only RCT including participants with this type of
10
classification (that is, all the other RCTs enrolled TNM stage III antibody, and imatinib (NCT01782508), a c-KIT inhibitor. An-
participants exclusively on the basis of pathological evaluation). other trial is investigating the effect of interferon in participants
with ulcerated primary melanomas (EORTC 18081).

Studies awaiting classification

There are no studies awaiting classification.
Ongoing studies
Two ongoing studies are comparing interferon treatment with new
drugs: ipilimumab (ECOG E1609), an anti-CTLA-4 monoclonal
Risk of bias in included studies
Figure 2 summarises the risk of bias for each included study. Al-
though detailed descriptions of random sequence generation and
allocation concealment were often missing, the quality of the avail-
able evidence was generally good except for Rusciani 1997.

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 11

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 2. ’Risk of bias’ summary: review authors’ judgments about each ’Risk of bias’ item for each included
study

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 12

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Random sequence generation (selection bias)
Information regarding random sequence generation was unclear
in nine studies. In the other eight studies, we judged this item at
’low risk of bias’. In Rusciani 1997, the risk of selection bias was
high as it was unclear whether participants were randomly assigned
to control or treatment. Because of this lack of clarity, the authors
were contacted by phone and confirmed the randomised design,
but omitted information regarding the possible risk of selection
bias.
Allocation
Seven of the eligible studies under-reported allocation conceal-
ment, so we judged the risk of this type of bias as ’unclear’. In
the other 10 studies, we judged this item at ’low risk of bias’. In
Rusciani 1997, the risk of selection bias was high, as we have re-
ported above.
Blinding
Trials were not conducted in a blinded fashion, neither for the
participants nor for the investigators. However, this is not expected
to affect the primary aims of the study, i.e. disease-free and overall
survival, although some concerns may arise for other end points,
such as toxicity and quality of life.
Incomplete outcome data
The risk of attrition bias was low for the majority of the studies.
Missing outcome data were balanced in numbers across the inter-
vention and observation groups, with similar reasons for missing
data across groups.
Selective reporting
The main outcomes of the studies were disease-free survival, over-
all survival, or both: One or both of these outcomes have been
investigated according to the study design of each trial. In partic-
ular, two trials did not report data about the effect of interferon
alpha on participant overall survival as they had been designed by
the investigators to address only the issue of disease-free survival
(Kirkwood 2001a; Pehamberger 1998). Finally, the above-men-
tioned Rusciani 1997 did not report any survival data (i.e. time-
to-event data).
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Other potential sources of bias
Since we did not identify any other potential sources of bias, we
judged all the trials as at low risk of bias for this domain.
Effects of interventions
See: Summary of findings for the main comparison
Disease-free survival (DFS)
All 17 eligible trials (Agarwala 2011; Cameron 2001; Cascinelli
2001; Creagan 1995; Eggermont 2005; Eggermont 2008; Garbe
2008; Grob 1998; Hancock 2004; Hansson 2011; Kirkwood
1996; Kirkwood 2000; Kirkwood 2001; Kirkwood 2001a;
Kleeberg 2004; McMasters 2008; Pehamberger 1998), enrolling
10,345 participants, reported data on DFS.
The meta-analysis of these 17 RCTs (Analysis 1.1) showed a sig-
nificant risk reduction (17%) in participants undergoing postop-
erative interferon compared to those undergoing observation (15
trials) or other adjuvant therapy (HR = 0.83; CI 0.78 to 0.87;
Z-test P value < 0.0001). Between-study heterogeneity was not
statistically significant (I² statistic = 16%; Q-test P value = 0.27).
The ’leave-one-out’ sensitivity analysis showed no dominant RCT,
which demonstrates that the overall effect estimate is not affected
by the findings of a single RCT.
Upon exclusion of the 2 RCTs with an active control arm
(Kirkwood 2001; Kirkwood 2001a), the results were very similar
to those obtained including all 17 RCTs (HR = 0.84; CI 0.79 to
0.89; Z-test P value < 0.0001; I² statistic = 2%, Q-test P value =
0.43).
As shown in Figure 3, a small study effect was likely to be present
(Begg test P = 0.17; Egger test P = 0.03), and the ’trim & fill’
procedure revealed that 6 studies might be missing: Their addition
to the meta-analysis would reduce, but not nullify, the overall
effect of interferon on DFS (adjusted HR = 0.87; CI 0.83 to
0.92). On the other hand, upon exclusion of RCTs enrolling fewer
than 400 participants (Cameron 2001; Creagan 1995; Kirkwood
1996; Kirkwood 2001a; McMasters 2008; Pehamberger 1998),
the meta-analysis yielded results very similar to those obtained
including all RCTs (HR = 0.85; CI 0.80 to 0.90; Z-test P value <
0.0001; I² statistic = 20%; Q-test P value = 0.25).
13
 Figure 3. Funnel plot of comparison: 1 Interferon alpha versus any other comparator; outcome: 1.1
Disease-free survival (DFS)

Finally, although we found no significant heterogeneity, we used

subgroup analysis and metaregression to investigate whether some
study design features might have affected trial outcomes. We report
the results of all these analyses in Table 3 (for metaregression, see
also Figure 4 and Figure 5). Overall, we found that none of the
assessable factors we considered (interferon dose, TNM stage, year
of publication, and treatment duration) significantly affected the
impact of interferon on participants’ DFS.

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 14

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 4. Metaregression: interferon effect (log hazard ratio, Y-axis) on disease-free survival versus
treatment duration (months, X-axis). See for statistical details. Each circle represents a randomised controlled
trial (the circle size is proportional to the trial weight)

Figure 5. Metaregression: interferon effect (log hazard ratio, Y-axis) on disease-free survival versus
publication year (year, X-axis). See for statistical details. Each circle represents a randomised controlled trial
(the circle size is proportional to the trial weight)

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 15

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Overall survival (OS)
Fifteen out of 17 eligible trials (Agarwala 2011; Cameron 2001;
Cascinelli 2001; Creagan 1995; Eggermont 2005; Eggermont
2008; Garbe 2008; Grob 1998; Hancock 2004; Hansson 2011;
Kirkwood 1996; Kirkwood 2000; Kirkwood 2001; Kleeberg
2004; McMasters 2008), enrolling 9927 participants, reported
data on OS.
The meta-analysis of these 15 RCTs (Analysis 1.2) showed a sig-
nificant risk reduction (9%) in participants undergoing postop-
erative interferon compared to those undergoing observation (14
trials) or other adjuvant therapy (HR = 0.91; CI 0.85 to 0.97; Z-
test P value = 0.003). Between-study heterogeneity was not statis-
tically significant (I² statistic = 6%; Q-test P value = 0.38).
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). This means that, given a group of 35 par-
ticipants with high-risk melanoma treated with interferon, after 5
years of follow-up, 22 participants would be alive; in contrast, in
a group of 35 participants not treated with interferon, 21 partici-
pants would be alive.
The ’leave-one-out’ sensitivity analysis showed no dominant RCT,
which demonstrates that the overall effect estimate is not affected
by the findings of a single RCT.
Upon exclusion of the RCT with an active control arm (Kirkwood
2001), the results were very similar to those obtained including all
15 RCTs (HR = 0.92; CI 0.86 to 0.98; Z-test P value = 0.01; I²
statistic = 0%; Q-test P value = 0.46).
As shown in Figure 6, a small study effect was likely to be present
(Begg test P = 0.07; Egger test P = 0.06); however, the ’trim
& fill’ procedure suggested that no study is missing. On the
other hand, upon exclusion of RCTs enrolling fewer than 400
participants (Cameron 2001; Creagan 1995; Kirkwood 1996;
McMasters 2008), the meta-analysis yielded results very similar to
those obtained including all RCTs (HR = 0.92; CI 0.86 to 0.98;
Z-test P value = 0.012; I² statistic = 19%; Q-test P value = 0.26).

Figure 6. Funnel plot of comparison: 1 Interferon alpha versus any other comparator; outcome: 1.2 Overall
survival (OS)

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 16

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Finally, although we found no significant heterogeneity, we used
subgroup analysis and metaregression to investigate whether some
study design features might have affected trial outcomes. We re-
port the results of all of these analyses in Table 4. According to
subgroup analysis, interferon is not associated with an OS ben-
efit in participants with AJCC TNM stage III melanoma (that
is, in participants with regional lymph node metastasis), whereas
the OS advantage is maintained in trials including both partici-
pants with stage III and those with stage II disease (that is, with-
out lymph node metastasis). Only one trial enrolled exclusively
AJCC TNM stage II participants and reported OS data, which
did not enable us to perform subgroup analysis in this subset of
participants. It should also be noted that the heterogeneity analy-
sis did not show any significant difference between the summary
hazard ratios (HR) of the three groups of trials (i.e. those enrolling
participants with AJCC TNM stage II, stage III, and stage II-III,
respectively). With regard to interferon dose, subgroup analysis
suggested that interferon is not associated with an OS benefit in
participants treated with high- or intermediate-dose, whereas the
OS advantage is maintained in trials enrolling participants treated
with low-dose interferon. Also in this case, the heterogeneity anal-
ysis did not show any significant difference between the summary
HR of the three groups of trials (i.e. those treating participants
with high-, intermediate-, or low-dose interferon, respectively). A
metaregression showed neither year of publication nor treatment
duration appeared to have any significant impact on the magni-
tude of treatment effect (Table 4).
DISCUSSION
Summary of main results
The results of this meta-analysis support the efficacy of adjuvant
interferon alpha (interferon) for the treatment of people with high-
risk (AJCC TNM stage II-III) cutaneous melanoma in terms of
both disease-free survival (DFS) and - to a lesser extent - overall
survival (OS). In fact, the risk reduction associated with interferon
administration was statistically significant for both DFS (17%,
95% CI 13 to 22%) and OS (9%, 95% CI 3 to 15%) (Summary
of findings for the main comparison).
The results of subgroup analysis failed to answer the questions
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 ben-
efit more from this postoperative adjuvant therapy.
High-grade toxicity (i.e. Grades 3 and 4) was observed in a minor-
ity 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
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
quality of life, toxicity disappeared after treatment discontinua-
tion.
Overall completeness and applicability of
evidence
Although this meta-analysis showed that interferon is associated
with a better survival, it failed to identify the optimal interferon
dosage and schedules. The available evidence is unsuitable to fully
address the issue of the impact of interferon on the quality of life
of the treated participants.
Interferon dosage and schedules
While the studies included in this meta-analysis are sufficient to
prove the effect of interferon in reducing risk of disease progression
and death among high-risk people, it is still necessary to identify
optimal treatment dosages and schedules and to improve patient
selection. With regard to interferon dosage, findings from our
subgroup analyses (see Table 3 and Table 4) indicate that interferon
is equally effective in terms of DFS when different doses (i.e. high
versus low versus intermediate) are administered.
In contrast, when it comes to OS, the therapeutic benefit remains
statistically significant only when considering trials that used low-
dose interferon. This finding is in contrast with the common be-
lief that high-dose interferon is the most effective, which has led
the US Food and Drug Administration (FDA) and the European
Medicines Agency (EMA) to approve high-dose interferon and
pegylated interferon. This is supported by the results of a RCT ad-
dressing this issue, which compared high-dose versus low-dose in-
terferon, and showed that the low-dose interferon regimen was as-
sociated with advantage in DFS, but not in OS (Kirkwood 2000).
Our findings appear to challenge this but leave the debate open,
since the low statistical power might be the reason why the sub-
group analysis of our meta-analysis failed to detect a significant
risk reduction: In other words, the number of RCTs needed to
detect a relatively small OS advantage (such as that observed in
this meta-analysis) might be higher than the number of RCTs cur-
rently available.
It is important to remember that some RCTs (Hansson 2011;
Kirkwood 1996) directly addressed this issue by randomly assign-
ing participants to different interferon doses, but we had to ex-
clude the following from this review as they did not fulfil the
inclusion criteria: Chiarion-Sileni 2011; Grob 2010; Hauschild
2009; Pectasides 2009. However, none of them demonstrated
that the classical E1684 regimen (i.e. high-dose induction + low-
dose maintenance) (Kirkwood 1996) yields results different from
the E1684 maintenance phase alone (Hauschild 2009) or that
an intensified high-dose interferon regimen (4 courses of induc-
tion phase every other month) is any better than the classical
E1684 full regimen (1-month induction + 11-month mainte-
nance) (Chiarion-Sileni 2011), or that the E1684 full regimen is
superior to the E1684 induction phase alone (Pectasides 2009).
17
The results of these trials cannot be pooled in a meta-analysis since
the study designs are too heterogeneous.
Analogously, we could not define whether the duration of inter-
feron treatment impacts on its efficacy: In fact, metaregression
analysis did not show any significant relationship between inter-
feron treatment duration and DFS or OS benefit (see Table 3
and Table 4). The results of the EORTC trial published in 2005
(Eggermont 2005) showed that intermediate-dose interferon pro-
longed DFS (as compared to observation) only when administered
for 2 years (and not for 1 year), although no effect on OS was
observed. Nevertheless, four other RCTs that addressed this issue
did not detect any statistically significant difference between the
following:
1. the original E1684 full regimen (high-dose for 1 month +
low-dose for 11 months) versus an intermittent schedule (3
courses of high-dose for 1 month repeated every 4 months)
(Mohr 2008);
2. intermediate-dose interferon for 1 year compared to 2 years
(Hansson 2011);
3. a low-dose interferon regimen for 18 months versus the
same for 60 months (Hauschild 2010); or
4. low-dose interferon for 18 months versus a similar regimen
(pegylated interferon 100 mcg subcutaneously once weekly) for
36 months (Grob 2010).
Also, the results of these trials cannot not be pooled in a meta-
analysis since the study designs are too heterogeneous.
Finally, we could not exhaustively answer the question of whether
interferon treatment is more effective in a specific disease stage
(i.e. AJCC TNM stage II (negative lymph nodes) versus stage
III (positive nodes)). In fact, considering disease-free survival as
the end point, interferon appeared to be equally effective. How-
ever, when overall survival was taken into consideration, RCTs en-
rolling exclusively stage III participants showed no survival advan-
tage (Table 4), whereas RCTs indiscriminately enrolling partici-
pants with stage II or stage III disease did demonstrate an overall
survival benefit (Table 4), and the only RCT exclusively enrolling
stage II participants was positive in terms of overall survival (Grob
2010). Overall, our findings might suggest that interferon adju-
vant therapy is more effective in stage II melanoma patients, but
the evidence supporting this hypothesis is too scarce to draw any
definitive conclusion.
Toxity and quality of life
Severe adverse events (Grades 3 and 4 according to the scale
adopted by the World Health Organization) after treatment with
interferon occurred in the minority of the included studies (Table
5), with Grade 3 fever (0% to 8%) and fatigue (0% to 23%) being
the most frequently observed adverse events.
Side-effects such as these impair quality of life (QoL) as reported
by some other studies that investigated quality of life after treat-
ment with interferon (Bottomley 2009 based on Eggermont 2008;
Ziefle 2011a based on Hauschild 2010; and Brandberg 2012 based
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
on Hansson 2011). Results favoured the treatment with interferon
over observation in terms of quality of life-adjusted survival (Cole
1996 based on Kirkwood 1996; Kilbridge 2001 and Kilbridge
2002 based on both Kirkwood 1996 and Kirkwood 2000; and
Caraceni 1998 based on Cascinelli 2001). In the pivotal trial of
the Eastern Cooperative Oncology Group, the E1684 (Kirkwood
1996), Cole et al studied the effect of quality of life on patient sur-
vival and showed that although interferon improved disease-free
and overall survival by 9 and 7 months, respectively, it caused 6
months of significant toxicity (Cole 1996). However, participants
treated with interferon had a better quality of life-adjusted survival
than participants who were observed only, regardless of their rela-
tive valuations for toxicity and disease-free survival. This difference
was statistically significant only for participants who considered
toxicity to have a high relative value and disease relapse to have a
low relative value, but not for participants who valued toxicity the
same as relapse. Another study conducted on participants of the
E1684 trial compared the quality of life of participants who expe-
rienced severe toxicity during treatment with interferon (Grade 4)
with that of participants who had a recurrence in the observation
arm, showing that participants rated quality of life with melanoma
recurrence lower than even severe toxicity (Kilbridge 2001).
A quality of life-adjusted survival analysis conducted in a subgroup
of participants enrolled in 2 of the included studies (Kirkwood
1996; Kirkwood 2000) suggested that interferon may improve
quality of life-adjusted survival for some, but only a minority
(16%) showed a statistically significant benefit. The change in
quality of life-adjusted survival depends more on the measure for
interferon toxicity than on the measure for melanoma recurrence
(Kilbridge 2002). Taken together, these data showed that although
interferon alpha negatively affects quality of life, there is an im-
provement in quality of life-adjusted survival for those who un-
dergo treatment with interferon. The occurrence of toxicity and
its negative effect on quality of life can be managed as suggested
by expert authors (Bottomley 2009; Hauschild 2008), and it is
reversible when the treatment is stopped (Brandberg 2012).
Of note, differences in assessment of quality of life prevented
meta-analysis of quality of life measures. Currently, there is still a
lack of a melanoma-oriented questionnaire that could account for
changes in quality of life in subsets of patients (Cormier 2012).
Beside the cancer questionnaire QLQ-C30 of the European Or-
ganisation for Research and Treatment of Cancer (EORTC), only
two QoL questionnaires have been designed specifically for peo-
ple who have melanoma: the FACT-Melanoma, which does not
include evaluation of psychological domains, and the Malignant
Melanoma Module, which has not been validated yet (Cormier
2011; Winstanley 2013). A new instrument for assessing quality
of life of people with melanoma, but which is not addressing in-
terferon and adjuvant treatment specifically, is under evaluation
within the Quality of Life Group of the EORTC.
18
Quality of the evidence
This body of evidence allows us to draw robust conclusions re-
garding the impact of interferon alpha on disease-free and overall
survival of high-risk melanoma patients. We included 18 studies,
with 10,499 participants: Of these, we were able to perform meta-
analyses for disease-free survival on 10,345 participants from 17
studies and overall survival on 9927 participants from 15 stud-
ies; 2 studies had not been designed to investigate overall survival,
and 1 included study of 154 participants did not assess either
outcome. The evidence we collected comes from well-designed
randomised controlled trials (RCTs) most often conducted by in-
ternational organisations, e.g. the European Organization for Re-
search and Treatment of Cancer (EORTC), and the Eastern Co-
operative Oncology Group (ECOG). Therefore, the quality of the
evidence meta-analysed in the present work can be considered high
(Summary of findings for the main comparison).
Potential biases in the review process
There was a generally low risk of bias in all the eligible studies, but
one (Rusciani 1997) that was not suitable for inclusion in the meta-
analysis. Selection bias was difficult to ascertain in roughly half
of the studies as no information was reported in the manuscripts.
Finally, no trial was conducted in a blinded fashion. Although this
is not supposed to affect survival, which is the primary end point
of all studies, issues may arise regarding toxicity and quality of life.
Agreements and disagreements with other
studies or reviews
Our findings support the efficacy of adjuvant interferon alpha
(interferon) for the treatment of people with high-risk (AJCC
TNM stage II-III) cutaneous melanoma in terms of both disease-
free survival (DFS) and, to a lesser extent, overall survival (OS).
These results represent a significant update of the existing literature
on this subject: In fact, compared to previous meta-analyses, the
present work includes 3 new RCTs (Agarwala 2011; Hansson
2011; McMasters 2008) and can count on the survival data of
10,345 participants.
Out of three previous meta-analyses of adjuvant interferon for
melanoma patients (Pirard 2004; Mocellin 2010; Wheatley 2003),
the first two reported a disease-free survival advantage but not an
overall survival benefit (Pirard 2004; Wheatley 2003). In partic-
ular, Pirard and colleagues (Pirard 2004) considered nine trials
including the two studies with severe drawbacks in their design,
which we excluded from the present meta-analysis (see Excluded
studies). These investigators measured the risk of both disease re-
currence and death by calculating odds ratios (OR: the ratio be-
tween odds, where “odds” indicates the ratio between events and
non-events in a given participant group): This is an inappropri-
ate method to study survival data (also called time-to-event data),
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
which are better described by hazard ratios (HR: the ratio between
the risks of an event occurring over a given time span, where “haz-
ard” indicates the risk in a given participant population). This is
especially true when considering the OS data because in the long-
term, all participants of both comparison arms will die of disease
or any other cause; thus, no therapy-induced benefit could ever be
detected using statistics based exclusively on the number of events.
In the second full-text meta-analysis, Wheatley and colleagues
(Wheatley 2003) used time-to-event data and found a DFS (but
not OS) advantage including 12 RCTs, but not the 2 trials we
judged ineligible (Kokoschka 1990; Rusciani 1997). For three in-
cluded RCTs (Eggermont 2005; Hancock 2004; Kleeberg 2004),
these authors could not use the definitive data because the articles
reporting them were published after their meta-analysis was pub-
lished. Later on, the same authors published an abstract describ-
ing an individual patient data meta-analysis on the same subject
(Wheatley 2007), considering 13 RCTs and 6067 participants;
these investigators showed a benefit in terms of both DFS (OR =
0.87; 95% CI 0.81 to 0.93) and OS (OR = 0.9; 95% CI 0.84 to
0.97).
Finally, in a meta-analysis published in 2010, Mocellin and col-
leagues considered 14 RCTs (including 2 trials published after the
last work of Wheatley and colleagues (Eggermont 2008; Garbe
2008) and including 8122 participants: They also found that in-
terferon significantly improves both DFS (risk reduction = 18%)
and OS (risk reduction = 11%) of participants with high-risk cu-
taneous melanoma (Mocellin 2010).
AUTHORS’ CONCLUSIONS
Implications for practice
Our findings support the efficacy of adjuvant interferon alpha (in-
terferon) 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 re-
ported relief from symptoms and improvement in quality of life
after treatment discontinuation.
Until better selection methods or more effective therapies are avail-
able, 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
19
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 treat-
ment:
• About 40% of AJCC TNM stage II-III participants are
likely to be cured with surgery alone; thus, it is unnecessary to
expose them to the toxicity of interferon therapy. Moreover, their
inclusion in interferon trials could represent a bias in evaluating
interferon efficacy since they would never benefit from this
treatment and thus would only dilute the survival advantage
associated with the administration of this cytokine to those who
do harbour minimal residual disease after surgery. This issue can
be addressed by developing effective methods to detect minimal
residual disease after apparently radical surgery of high-risk
melanoma: In this regard, detection of circulating tumour cells
in the peripheral blood is being advocated as a promising tool to
select melanoma patients most likely to need adjuvant treatments
(Mocellin 2006). As a further example, some investigators have
proposed ulceration as a histopathological marker of tumour
aggressiveness (and thus as a predictor of minimal residual
disease) (Eggermont 2011). A planned trial will test the
hypothesis that interferon might be more effective in this subset
of participants (the EORTC 18081, which will compare
adjuvant pegylated interferon in sentinel node-negative AJCC
stage II and IIIA participants with ulcerated primary tumours).
B) By elucidating the molecular mechanisms underlying
melanoma responsiveness to interferon:
• This would allow physicians to administer interferon
selectively to people most likely to be responsive to interferon
(Brown 2006; Foser 2006; Kumar 2007; Lesinski 2008; Lesinski
2010; Rao 2010; Wang 2008). For instance, in a recent report it
has been suggested that multiplexed analysis of serum
biomarkers (interleukin (IL)-1alpha, IL-1beta, IL-6, IL-8, IL-
12p40, IL-13, granulocyte-macrophage colony-stimulating
factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-
1), macrophage inflammatory protein (MIP)-1alpha, MIP-
1beta, interferon, tumour necrosis factor (TNF)-alpha,
epidermal growth factor (EGF), vascular endothelial growth
factor (VEGF), and TNF receptor II) might become a useful
tool for predicting response to interferon of patients with high-
risk operable melanoma (Yurkovetsky 2007a).
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
C) By developing new treatments that are more effective than
interferon against minimal residual disease.
• In this regard, great expectations are obviously set on anti-
melanoma molecularly targeted therapies (Friedlander 2010;
Mocellin 2010a); recent successes with small-molecule BRAF
inhibitors (Hodi 2010) and anti-CTLA-4 monoclonal antibodies
(Chapman 2011) in people with metastatic melanoma are
fuelling new hopes, although no data are yet available in the
adjuvant setting.
Until better selection methods or more effective therapies are avail-
able, 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 carci-
nomas, 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 tu-
mour types.
Finally, the findings of this meta-analysis support interferon alpha
as the reference treatment in RCTs investigating new therapeu-
tic agents for the adjuvant treatment of high-risk melanoma par-
ticipants. 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).
ACKNOWLEDGEMENTS
We truly thank our data manager (Dr Marta Briarava) for her help
in retrieving scientific articles and for setting up the database we
used to collect and analyse the data from clinical trials. We also
thank the Cochrane Skin Group, and in particular Prof Hywel
Williams, Miss Laura Prescott, and Dr Finola Delamere for their
assistance.
The Cochrane Skin Group editorial base wishes to thank Dedee
Murrell who was the Key Editor for this review; Jo Leonardi-Bee
and Philippa Middleton who were the Statistical and Methods
Editors, respectively; the clinical referees, Eleni Linos and Rubeta
Matin; and the consumer referee, Kathie Godfrey.
20
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∗
Indicates the major publication for the study
27
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Agarwala 2011

Methods 553 centres enrolled participants

Accrual period: 1998 to 2010
Design: phase III randomised controlled trial (RCT)

Participants Number of participants: 1150

Observation N = 569 (group A); interferon alpha 2b N = 581 (group B)
Participants randomised: 1150
Participants evaluable: 1150
Inclusion criteria of the trial
• participants with histologically proven melanoma > 1.5/2 mm thick or melanoma
(> T3 tumour according to 6th and 7th edition of the AJCC TNM staging system)
• participants with negative lymph node or with regional lymph metastasis detected
with sentinel node biopsy (AJCC TNM stages N1a and N2a)
Exclusion criteria of the trial
• evidence of distant metastasis
• a history of prior malignant disease (except basal cell carcinoma of the skin or
surgically treated early carcinoma of the cervix)
• poor performance status
• vital organ dysfunction

Interventions • Group A: observation

• Group B: high-dose interferon alpha 2b (20 MU/m²) intravenously (i.v.) over 20
minutes daily for 5 consecutive days for 4 weeks

Outcomes 1. Disease-free survival (DFS): No difference between arms was observed

2. Overall survival (OS): No difference between arms was observed
Subgroup analysis: not performed

Notes Median follow-up: not known

Participants with lymph node metastasis: histopathological status of lymph node was
known in 1035 participants (90%). Sentinel node biopsy and elective lymph node dis-
section were performed in 955 (83%) and 122 (11%), respectively. Lymph node metas-
tasis were detected in 101 (20%) and 95 (18%) in the observation and interferon arms,
respectively
Dose reduction/treatment discontinuation: no available data
Quality of life: According to the protocol, it was assessed before treatment at day 22,
every 3 months for 2 years, and then every 6 months for 3 years (results not reported)

Risk of bias

Bias Authors’ judgement Support for judgement

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 28

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Agarwala 2011 (Continued)

Random sequence generation (selection Unclear risk There was insufficient information about
bias) the sequence generation process to permit
judgment

Allocation concealment (selection bias) Unclear risk There was insufficient information to per-
mit judgment

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Unclear risk There was insufficient reporting of attri-
All outcomes tion/exclusions to permit judgment

Selective reporting (reporting bias) Unclear risk There was insufficient reporting of attri-
tion/exclusions to permit judgment

Other bias Low risk There was insufficient information to assess

whether an important risk of bias existed,
but we judged this study to be free of other
sources of bias

Cameron 2001

Methods 9 centres enrolled participants

Accrual period: not reported
Design: phase III randomised controlled trial (RCT)

Participants Number of participants: 96

Interferon alpha 2b N = 46 (group A); observation N = 49 (group B)
Participants randomised: 96
Participants evaluable: 94
Inclusion criteria of the trial
• participants with histologically proven melanoma at least 3 mm thick or
melanoma participants undergoing radical lymph node dissection (RLND) for regional
lymph metastasis detected clinically and confirmed pathologically
Exclusion criteria of the trial
• clinically positive lymph node
• evidence of distant metastasis
• a history of prior malignant disease in the last 5 years (except basal cell carcinoma
of the skin or in situ tumours)
• poor performance status
• vital organ dysfunction
• previous or concomitant chemotherapy, immunotherapy, and radiotherapy

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 29

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cameron 2001 (Continued)

Interventions • Group A: interferon alpha 2a, 3 MU given subcutaneously (s.c.) 3 times per week
for 6 months
• Group B: observation

Outcomes 1. Disease-free survival (DFS): No difference between arms was observed

2. Overall survival (OS): No differences between arms was observed
Subgroup analysis: not performed

Notes Median follow-up: 78 months

Participants with lymph node metastasis: not reported
Dose reduction/treatment discontinuation: 3 participants (7%) required dose reduction
(2 for neutropenia and 1 for drug-related fever); treatment was stopped in 13 (28%)
cases following disease recurrence
Quality of life: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were randomized”
bias) Comment: There was insufficient informa-
tion about the sequence generation process
to permit judgment

Allocation concealment (selection bias) Unclear risk There was insufficient information to per-
mit judgment

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 30

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cascinelli 2001

Methods 23 centres belonging to the World Health Organization (WHO) Melanoma Programme
enrolled participants
Accrual period: 1990 to 1993
Design: phase III RCT

Participants Number of participants: 444

Interferon alpha 2a N = 225 (group A); observation N = 219 (group C)
Randomised: 444
Inclusion criteria of the trial
• participants with primary melanoma and regional lymph node metastasis
• age between 18 and 70 years
• absence of residual disease at the primary site or distant sites beyond the draining
nodes
Exclusion criteria of the trial
• any other malignant disease (apart from basal cell carcinoma)
• absence of cardiac, metabolic, neurological, or vascular disease (contraindicating
long-term use of interferon alpha)
• previous non-surgical treatment for melanoma
• previous exposure to interferon alpha 2a
• concomitant use of corticosteroids or other investigational drugs

Interventions • Group A: 3 MU s.c. of interferon alpha 2a 3 times per week for 3 years
• Group B: observation

Outcomes 1. Disease-free survival: not significant

2. Overall survival: not significant
Subgroup analyses: not reported

Notes Median follow-up: 88

Lymph node dissection was performed following the guidelines produced by the educa-
tion project of the WHO Melanoma Programme
Participants with lymph node metastasis: 100%
Dose reduction/treatment discontinuation: not reported
Quality of life: Interferon has no negative effect on quality of life or daily activities of
treated participants; fatigue and anxiety were more frequent in the interferon alpha 2a
group than in those who had surgery alone

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “eligible patients were randomly as-
bias) signed”
Comment: There was insufficient informa-
tion about the sequence generation process
to permit judgment

Allocation concealment (selection bias) Low risk The trial used central allocation

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 31

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Cascinelli 2001 (Continued)

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Creagan 1995

Methods The North Central Cancer Treatment Group and the Mayo Clinic conducted this study
Accrual period: 1984 to 1990
Design: phase III RCT

Participants Number of participants: 266

High-dose interferon alpha 2b N = 132 (group A); observation N = 132 (group B)
Participants randomised: 264
Participants evaluable: 264
Inclusion criteria of the trial
• primary melanoma > 1.69 mm thick with clinically negative lymph nodes or
positive nodes after lymphadenectomy
Exclusion criteria of the trial
• any malignant tumour within the previous 3 years, except superficial squamous or
basal cell carcinoma and in situ carcinoma of the cervix
• evidence of unresected distant or regional disease

Interventions • Group A: high-dose interferon alpha 2a 20 MU/m² × 3/week for 4 months i.m.
• Group B: observation

Outcomes 1. Disease-free survival: There was no significant disease-free survival benefit for
participants treated with interferon
2. Overall survival: There was no significant overall survival benefit for participants
treated with interferon
Subgroup analysis: There was a significant disease-free survival benefit for participants
with lymph node metastasis

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Creagan 1995 (Continued)

Notes Median follow-up: 73 months

Lymph node dissection: Lymphadenectomy was performed in case of clinically positive
lymph node
Participants with lymph node metastasis: 62%
Dose reduction/treatment discontinuation: More than half of participants (no quantifi-
cation has been provided) required dose modification
Quality of life: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients randomized”

bias) Comment: There was insufficient informa-
tion about the sequence generation process
to permit judgment

Allocation concealment (selection bias) Unclear risk There was insufficient information to per-
mit judgment

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 33

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Eggermont 2005

Methods The trial was performed on behalf of the European Organization for Research and
Treatment of Cancer (EORTC). 85 institutions in 22 countries enrolled participants
Accrual period: 1996 to 2000
Design: phase III RCT

Participants Number of participants: 1418

13-month interferon alpha 2b N = 553 (group A); 25-month interferon alpha 2b N =
556 (group B); observation N = 279 (group C)
Participants randomised: 1388
Inclusion criteria of the trial
• age 18 to 75 years
• AJCC stage IIb-III
Exclusion criteria of the trial
• participants with mucosal or ocular melanoma
• participants previously treated with systemic drugs for melanoma
• participants with other malignant diseases (other than basal cell carcinoma, in situ
cervical cancer), autoimmune disease, uncontrolled infections, cardiopulmonary
disease, or liver or renal disease
• participants taking corticosteroids

Interventions • Group A: 4 weeks of 10 MU of interferon (5 days per week), followed by 10 MU

3 times per week for 1 year
• Group B: 4 weeks of 10 MU of interferon (5 days per week), followed by 5 MU 3
times per week for 2 years
• Group C: observation

Outcomes 1. Distant metastasis-free interval (time form randomisation to appearance of distant

metastasis): There were no differences between participants enrolled in the treatment
arms
2. Distant metastasis-free survival (time from randomisation to distant metastasis or
death): There were no differences between participants enrolled in the treatment arms
Subgroup analysis: node-negative participants (AJCC stage IIb) treated with interferon
alpha 2b for 25 months had a better distant metastasis-free interval and survival than
participants enrolled in the observation arm

Notes Median follow-up: 56 months

Lymph node dissection: Regional lymph node dissection had to contain more than 5
nodes (inguinal), more than 10 nodes (axillary), or more than 15 nodes (neck)
Participants with lymph node metastasis: 75%
Dose reduction/treatment discontinuation: 16% of participants treated with 13-months
of interferon and 20% of participants treated with 25-months of interferon
Quality of life: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

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Eggermont 2005 (Continued)

Random sequence generation (selection Low risk Quote: “We enrolled and randomly as-
bias) signed...”
Quote: “randomisation was done with
minimisation techniques”

Allocation concealment (selection bias) Low risk Quote: “randomisation was done centrally
from the EORTC data centre”

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes, including those that
were prespecified

Other bias Low risk The study appeared to be free of other

sources of bias

Eggermont 2008

Methods The trial was performed on behalf of the EORTC. 99 centres in 17 countries (mainly
in Europe) enrolled participants
Accrual period: information not reported
Design: phase III RCT

Participants Number of participants: 1256

Pegylated interferon alpha 2b N = 627 (group A); observation N = 629 (group B)
Participants randomised: 1256
Inclusion criteria of the trial
• age 18 to 70 years
• pathological AJCC stage III melanoma (TxN1-2M0)
• adequate surgical margins at wide excision of primary melanoma
• complete regional lymphadenectomy must have occurred 70 days or less before
randomisation
• normal liver, renal, and bone marrow function
Exclusion criteria of the trial
• ocular or mucous membrane melanoma

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Eggermont 2008 (Continued)

• evidence of distant metastasis or in-transit metastasis

• prior malignancy within the past 5 years (other than surgically resected non-
melanoma skin cancer or cervical carcinoma in situ)
• autoimmune disease
• uncontrolled infections, cardiovascular disease, liver or renal disease
• use of systemic corticosteroids
• previous use of systemic therapy for melanoma

Interventions • Group A: pegylated interferon alpha 2b was administered at 6 µg/kg per week s.c.
for 8 weeks (induction phase), followed by 3 µg/kg per week s.c. for an intended
treatment duration of 5 years (maintenance phase)
• Group B: observation

Outcomes 1. Disease-free survival: There was a significant difference in disease-free survival

between treatment arms (the 4 years survival were 45.6% in the interferon group versus
38.9% in the observation group). Distant metastasis disease-free survival was not
significantly different in participants treated with interferon or followed by observation
2. Overall survival: No significant difference was seen in overall survival between the
2 groups
Subgroup analyses: Pegylated interferon alpha seemed effective in prolonging disease-
free survival for participants with microscopic lymph node involvement (i.e. participants
with positive sentinel node biopsy)

Notes Median follow-up: 46 months

Lymph node dissection: Complete regional lymphadenectomy must have occurred 70
days or less before randomisation
Participants with lymph node metastasis: 100%
Dose reduction/treatment discontinuation: The study protocol specified stepwise dose
adjustments (6 µg/kg per week to 3, 2, and 1 µg/kg per week during the induction phase,
and from 3 µg/kg per week to 2 and 1 µg/kg per week during the maintenance phase)
to adjust for toxicity and to maintain an Eastern Cooperative Oncology Group (ECOG)
performance status of 0 or 1 for each participant. Treatment could be interrupted for
surgery for local or regional recurrence of melanoma, then resumed after surgery
Quality of life: Quality of life analysis, which has been reported elsewhere (Bottomley
2009), showed that pegylated interferon worsened patient quality of life. In particular,
there were important differences for 5 scales used to assess quality of life: 2 functioning
scales (social and role functioning) and 3 symptom scales (appetite loss, fatigue, and
dyspnea), with the pegylated interferon alpha 2b arm being most impaired

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “patients were randomly assigned”
bias) Quote: “randomisation was done with
minimisation techniques; the sequence was
generated by computer”

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Eggermont 2008 (Continued)

Allocation concealment (selection bias) Low risk Quote: “randomisation was done centrally
at the EORTC data centre”

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes, including those that
were prespecified

Other bias Low risk The study appeared to be free of other

sources of bias

Garbe 2008

Methods 42 centres belonging to the Dermatologic Cooperative Oncology Group (DeCOG)

network in Germany and Switzerland enrolled participants
Accrual period: 1997 to 2001
Design: phase III RCT

Participants Number of participants: 444

Interferon alpha 2a N = 148 (group A); interferon alpha 2a and dacarbazine (DTIC) N
= 148 (group B); observation N = 148 (group C)
Randomised: 444
Evaluable: 441
Inclusion criteria of the trial
• primary cutaneous malignant melanoma and pathologically proven regional node
metastases (either microscopic or macroscopic metastasis)
• complete lymphadenectomy and absence of satellite
• in-transit or distant metastases
• age between 18 and 75 years
• absence of any other malignant disease apart from basal cell carcinoma
• absence of cardiac, liver, renal, neurological, or autoimmune diseases
Exclusion criteria of the trial
• previous exposure to interferon alpha
• concomitant use of corticosteroids
• other investigational drug

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Garbe 2008 (Continued)

Interventions • Group A: 3 MU s.c. of interferon alpha 2a 3 times per week for 2 years
• Group B: 3 MU s.c. of interferon alpha 2a 3 times per week for 2 years, plus
DTIC 850 mg/m² every 4 to 8 weeks for 2 years
• Group C: observation

Outcomes 1. Disease-free survival: There was a significant improvement for participants treated
with interferon alone with respect to those who received interferon + DTIC or
observation
2. Overall survival: There was a significant improvement for participants treated with
interferon alone with respect to those who received interferon + DTIC or observation
Subgroup analyses: not reported

Notes Median follow-up: 47 months

Lymph node dissection: This was carried out before randomisation, according to the
German guidelines on the treatment of melanoma
Participants with lymph node metastasis: 100%
Dose reduction/treatment discontinuation: 21 participants withdrew their informed
consent
Quality of life: EORTC QLQ-C30 questionnaire scores at baseline and 6 months after
randomisation were compared in 238 participants. Participants under adjuvant treatment
had a better outcome for ’physical functioning’ (group A versus C: P=0.007), ’role
functioning’ (group A versus C: P=0.008), and ’emotional functioning’ (group A versus
C: P=0.048) in comparison to the participants treated with surgery only

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “patients were randomly assigned”
bias) Quote: “a permuted block randomization
list”

Allocation concealment (selection bias) Low risk The trial used central allocation

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

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Garbe 2008 (Continued)

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Grob 1998

Methods 31 centres in France enrolled participants

Accrual period: 1990 to 1994
Design: phase III RCT

Participants Number of participants: 499

Interferon alpha 2a N = 244 (group A); observation N = 243 (group B)
Participants randomised: 499
Participants evaluable: 487
Inclusion criteria of the trial
• age 18 to 75 years
• histologically proven melanoma > 1.5 mm thick treated by wide excision
Exclusion criteria of the trial
• clinically detectable regional node metastases
• visceral metastases
• previous treatment for melanoma except surgery
• history of other cancer except basal cell carcinoma
• white blood cell count < 4×10
/L, haemoglobin < 11 g/dL
• creatinine, bilirubin, aspartate aminotransferase, alanine aminotransferase, and
alkaline phosphatase concentrations < 1 to 5 times that of the upper limit of normal
range

Interventions • Group A: interferon alpha 2a 3 MU s.c. 3 times per week for 18 months
• Group B: observation

Outcomes 1. Disease-free survival: Participants treated with interferon alpha 2a had a

significantly longer DFS. The estimated hazard ratio showed a substantial reduction of
relapse risk in treated participants as compared to controls during the first 2 years of
follow-up
2. Overall survival: No significant difference was observed between treatment arms
Subgroup analyses: not reported

Notes Median follow-up: 60 months

Lymph node dissection: not reported
Participants with lymph node metastasis: Lymph node metastases were detected in 68
(28%) and 78 participants in the interferon and observation groups, respectively
Dose reduction/treatment discontinuation: Treatment was discontinued in 89 partici-
pants (36%): 43 relapsed; 7 refused further treatment; 3 were lost to follow-up; and 1
stopped because of a wrong diagnosis. 35 participants withdrew because of 1 or several

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Grob 1998 (Continued)

adverse events
Quality of life: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “Patients were randomly assigned”
bias) Quote: “The random-allocation list was
computer generated”

Allocation concealment (selection bias) Low risk The trial used central allocation

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Hancock 2004

Methods Participants were enrolled in the UK

Accrual period: 1995 to 2000
Design: phase III RCT

Participants Number of participants: 674

Interferon alpha 2a N = 338 (group A); observation N = 336 (group B)
Participants randomised: 674
Participants evaluable: 633
Inclusion criteria of the trial
• good performance status
• primary melanoma resection performed within 12 weeks before enrolment
Exclusion criteria of the trial
• history of other malignant disease

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Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Hancock 2004 (Continued)

• pregnancy or lactation
• biological therapy
• systemic corticosteroids or other immunosuppressive therapy

Interventions • Group A: interferon alpha 2a 3 MU s.c. 3 times per week for 24 months
• Group B: observation

Outcomes 1. Disease-free survival: There was no significant difference between the interferon
arm and the control arm
2. Overall survival: There was no significant difference between the interferon arm
and the control arm
Subgroup analysis: Younger participants (age < 50 years) treated with interferon had a
better DFS than younger participants untreated

Notes Median follow-up: 36 months

Lymph node dissection: No description of the adopted surgical protocol was reported
Participants with lymph node metastasis: 85 participants (13%) had lymph node metas-
tasis at the time of primary melanoma diagnosis
Dose reduction/treatment discontinuation: There were 50 withdrawals (14.8%) from
interferon therapy due to toxicity; 24 participants stopped therapy for reasons other than
toxicity, recurrence, or death from unrelated causes; dose reductions for toxicity were
recorded for 21 participants (5 subsequently withdrew from therapy); 15 participants (3
subsequently withdrew) had breaks in therapy due to toxicity
Quality of life: Interferon has significant effects on quality of life and symptomatology
and is unlikely to be cost-effective (Dixon 2006)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “Patients were randomly assigned”
bias) Quote: “Random assignments were bal-
anced by minimization”

Allocation concealment (selection bias) Low risk The trial used central allocation

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

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Hancock 2004 (Continued)

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appears to be free of other

sources of bias

Hansson 2011

Methods Participants were enrolled by 35 centres in Nordic countries: 2 in Denmark, 5 in Fin-

land, 6 in Norway, and 22 in Sweden. randomisation was done centrally at the data
management centre (Karolinska University Hospital, Stockholm, Sweden)
Design: phase III RCT

Participants Number of participants: 855

Observation N = 284 (group A); 1-year treatment with interferon alpha 2b N = 285
(group B); 2-year treatment with interferon alpha 2b N = 286 (group C)
Participants randomised: 855
Participants evaluable: 855
Inclusion criteria of the trial
• histologically verified resected cutaneous melanoma
• AJCC stage IIB-IIC (T4N0M0) or stage III (TxN1-3M0)
• age 18 years or older
• ECOG performance status 0 to 1
• normal bone marrow function
• adequate liver chemistry and renal function
Exclusion criteria of the trial
• non-cutaneous melanoma
• melanoma with unknown primary site
• incompletely resected melanoma
• second cancer diagnosis (except for basal cell and squamous cell skin cancer or in
situ cervical carcinoma)
• systemic corticosteroid medication
• pregnancy

Interventions • Group A: observation

• Group B: interferon alpha 2b 10 MU flat dose s.c. 5 days per week for 4 weeks
(induction), followed by interferon alpha 2b 10 MU flat dose s.c. 3 days per week for
12 months (maintenance)
• Group C: interferon alpha 2b 10 MU flat dose s.c. 5 days per week for 4 weeks
(induction), followed by interferon alpha 2b 10 MU flat dose s.c. 3 days per week for
24 months (maintenance)

Outcomes 1. Disease-free survival: Median DFS was 23.2 months in group A, 37.8 months in
group B, and 28.6 months in group C; the DFS difference between participants treated
with interferon and those receiving observation was statistically significant (P = 0.034)
2. Overall survival: Median OS differed between the groups (56.1 months in group
A, 72.1 months in group B, and 64.3 months in group C), but the difference was not

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Hansson 2011 (Continued)

statistically significant (P = 0.60)

Subgroup analysis: Participants without ulcerated primary tumours and treated with
interferon had benefit in terms of both DFS and OS. Participants with AJCC stage III
disease with clinically palpable lymph node metastases had improved DFS if treated with
interferon (P = 0.015)

Notes Median follow-up: 72.4 months

Lymph node dissection: Sentinel node biopsy (SNB) was not performed in all enrolled
participants as it was not routinely practised in enrolling countries. Elective lymph node
dissection was performed in the majority of participants, whereas few participants were
managed with sentinel node biopsy and completion lymph node dissection
Participants with lymph node metastasis: 80.6%
Dose reduction/treatment discontinuation: Dose reductions were reported in 164 (28.
7%) of the 571 participants randomly assigned to interferon alpha 2b therapy: 77 (27.
0%) in group B and 87 (30.4%) in group C. Interferon alpha 2b therapy was interrupted
or discontinued prematurely in 147 participants (25.7%): 75 (26.3%) in group B and
72 (25.2%) in group C
Quality of life: assessed with the EORTC QLQ-C30 questionnaire at 9 time points
from before randomisation to up to 2 years, with focus on the 6-month and 2-year
assessments. It was significantly negatively affected in almost all areas during treatment,
but levels similar to those in the control group were restored after the end of treatment

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “Patients were randomly assigned”
bias) Quote: “block randomisation, with block
size of 15”; “The allocation sequence was
computer-generated”

Allocation concealment (selection bias) Low risk The trial used central allocation

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was available, and all of
the study’s prespecified (primary and sec-
ondary) outcomes that were of interest in

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Hansson 2011 (Continued)

the review were reported in the prespecified

way

Other bias Low risk The study appeared to be free of other

sources of bias

Kirkwood 1996

Methods The study was conducted on behalf of the Eastern Cooperative Oncology Group
(ECOG) and United States (US) intergroup adjuvant studies
Accrual period: 1984 to 1990
Design: phase III RCT

Participants Number of participants: 287

High-dose interferon alpha 2b N = 147 (group A); observation N = 140 (group B)
Participants randomised: 287
Participants evaluable: 287
Inclusion criteria of the trial
• histologically proven AJCC stage IIB or stage III primary or recurrent regional
nodal involvement from cutaneous melanoma without evidence of systemic metastatic
disease
• normal organ function
• no significant medical or psychiatric comorbidity
• ECOG performance status of 0 or 1
Exclusion criteria of the trial
• history of adjuvant radiotherapy, chemotherapy, and immunotherapy

Interventions • Group A: high-dose interferon alpha 2b for 1 year (20 MU/m²/d i.v. 5 days/week
for 4 weeks; 10 MU/m² s.c. 3 days/week for 48 weeks)
• Group B: observation

Outcomes 1. Disease-free survival: There was a significant disease-free survival benefit for
participants treated with interferon by comparison with observed participants
2. Overall survival: There was a significant overall survival benefit for participants
treated with interferon by comparison with observed participants
Subgroup analysis: not performed

Notes Median follow-up: 83 months

Lymph node dissection: not available
Participants with lymph node metastasis: 89%
Dose reduction/treatment discontinuation: A dose reduction was observed in 35% of
participants; treatment discontinuation was necessary in 34% and 41% of participants
during induction and maintenance phases, respectively
Quality of life: Participants who received interferon alpha had more quality-of-life-
adjusted survival than the observation group, regardless of the relative valuations placed
on toxicity and relapse (Cole 1996)

Risk of bias

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Kirkwood 1996 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “Patients were randomized by per-
bias) muted blocks”

Allocation concealment (selection bias) Unclear risk There was insufficient information to per-
mit judgment

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Kirkwood 2000

Methods The study was conducted on behalf of the Eastern Cooperative Oncology Group
(ECOG) and United States (US) intergroup adjuvant studies
Accrual period: 1991 to 1995
Design: phase III RCT

Participants Number of participants: 642

High-dose interferon alpha 2b N = 215 (group A); low-dose interferon alpha 2b N =
215 (group B); observation N = 212 (group C)
Participants randomised: 642
Participants evaluable: 608
Inclusion criteria of the trial
• histologically proven AJCC stage IIB or stage III primary or recurrent regional
nodal involvement from cutaneous melanoma without evidence of systemic metastatic
disease
• normal organ function
• no significant medical or psychiatric comorbidity
• ECOG performance status of 0 or 1
Exclusion criteria of the trial

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Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kirkwood 2000 (Continued)

• history of adjuvant radiotherapy, chemotherapy, and immunotherapy

Interventions • Group A: high-dose interferon alpha 2b for 1 year (20 MU/m²/d i.v. 5 days/week
for 4 weeks; 10 MU/m² s.c. 3 days/week for 48 weeks)
• Group B: low-dose interferon alpha 2b (3 MU/d 3 days/week)
• Group C: observation

Outcomes 1. Disease-free survival: 5-year DFS was 44% in group A, 40% in group B, and 35%
in group C. High-dose interferon alpha 2b treatment is significantly superior to
observation, while no statistically significant difference is observed between the latter
and low-dose interferon alpha 2b
2. Overall survival: No significant difference was observed between treatment arms
and observation
Subgroup analysis: High-dose interferon alpha 2b was associated with a survival benefit
in participants with 2 to 3 positive lymph nodes

Notes Median follow-up: 52 months

Lymph node dissection: Participants with tumour depth > 4 mm and no clinical evidence
of lymph node metastasis were not required to undergo lymphadenectomy
Participants with lymph node metastasis: 75%
Dose reduction/treatment discontinuation: 58% of participants treated with high-dose
interferon alpha 2b required delay or dose reduction (44% due to toxicity). A significantly
larger proportion of relapsed participants from the observation arm (31%) received an
interferon-containing salvage regimen compared with only 15% of participants from the
high-dose interferon alpha 2b arm
Quality of life: 77% of participants would experience a benefit in quality-of-life-adjusted-
survival from interferon alpha, and 23% would experience a decrease in quality-of-life-
adjusted-survival, although these effects did not reach statistical significance (Kilbridge
2002)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Quote: “Patients were randomized by per-
bias) muted blocks”

Allocation concealment (selection bias) Unclear risk There was insufficient information to per-
mit judgment

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

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Kirkwood 2000 (Continued)

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Kirkwood 2001

Methods The study was conducted by Eastern Cooperative Oncology Group (ECOG) and United
States (US) intergroup adjuvant studies
Accrual period: 1996 to 1999
Design: phase III RCT

Participants Number of participants: 880

GMK N = 389 (group A); interferon alpha 2b N = 385 (group B)
Participants randomised: 774
Participants evaluable: 774
Inclusion criteria of the trial
• age > 18 years
• histologically proven AJCC stage IIB/III primary cutaneous melanoma or
clinically detected nodal metastasis arising from an unknown primary or a first
clinically detectable nodal recurrence
• without evidence of systemic metastases
• primary melanoma > 4.0 mm thick with microscopic satellite lesions within 2 cm
of the primary tumour
• normal organ function
• absence of significant medical or psychiatric comorbidity
• an ECOG performance status of 0 or 1
Exclusion criteria of the trial
• participants with gross subcutaneous invasion or grossly apparent satellite lesions
• prior adjuvant radiotherapy, chemotherapy, or immunotherapy
• contraindication to interferon usage
• pregnant or lactating women

Interventions • Group A: 1 ml of GMK vaccine administered s.c. on days 1, 8, 15, and 22, then
every 12 weeks (weeks 12 to 96)
• Group B: high-dose interferon alpha 2b, 20 MU/m²/d i.v. 5 days/week x 4 weeks
followed by 10 MU/m² s.c. 3 days/week x 48 weeks

Outcomes 1. Disease-free survival: High-dose interferon alpha 2b demonstrated a significant

DFS benefit with respect to GMK
2. Overall survival: High-dose interferon alpha 2b demonstrated a significant OS

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 47

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Kirkwood 2001 (Continued)

benefit with respect to GMK

Subgroup analyses: Node-negative participants had a statistically significant DFS and
OS benefit compared with participants treated with GMK

Notes Median follow-up: 16 months

Lymph node dissection: It was performed in case of clinically positive lymph node or
positive sentinel lymph node
Participants with lymph node metastasis: Lymph node involvement was documented
clinically or pathologically in 77% of participants
Dose reduction/treatment discontinuation: 45 participants in the interferon alpha 2b
arm (10%) discontinued treatment because of adverse events, while no participants
experienced treatment discontinuation, dose reduction, or both, in the GMK arm
Quality of life: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “patients were randomized”
bias) There was insufficient information about
the sequence generation process

Allocation concealment (selection bias) Low risk The trial used central allocation

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 48

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kirkwood 2001a

Methods The study was conducted on behalf of the Eastern Cooperative Oncology Group
(ECOG) and United States (US) intergroup adjuvant studies
Accrual period: -
Design: phase II RCT

Participants Number of participants: 107

Interferon alpha 2b and GMK vaccine starting on day 1 N = 36 (group A); GMK vaccine
starting from day 1 and interferon alpha 2b starting from week 5 N = 36 (group B);
GMK vaccine alone N = 35 (group C)
Participants randomised: 107
Participants evaluable: 107
Inclusion criteria of the trial
• age > 18 years
• free of disease after complete surgical resection for AJCC stage IIB, III, or IV
melanoma (including participants with resectable distant metastatic disease, regionally
advanced in-transit metastases, and extracapsular extension of nodal disease)
• participants with AJCC stage IIB-III disease ineligible for E1694 because more
than 56 days had elapsed since surgery
• enter this study within 1 year after surgery
• ECOG performance status < 2
• normal white blood cell and platelet counts
• AST (aspartate transaminase) and bilirubin ≤ 2 times the normal values
Exclusion criteria of the trial
• history of any prior systemic anticancer therapy (including immunemodulators)
• concomitant autoimmune or malignant disease
• anti-inflammatory immunosuppressive or antihistaminic drugs (including
corticosteroids)
• previous splenectomy
• history of heart disease higher than New York Heart Association (NYHA) class 2
• organic brain syndrome, neuropathy, or active infection
• history of severe allergic reaction to shellfish

Interventions • Group A: high-dose interferon alpha 2b, 20 MU/m²/d i.v. 5 days per week x 4
weeks, followed by 10 MU/m² s.c. 3 days per week x 48 weeks 1 mL plus GMK was
administered s.c. on weeks 1, 2, 3, 4, 12, 24, and 36 (each dose contained 30 µg of
GM2 and 100 µg of QS21). Both drugs were started on day 1
• Group B: high-dose interferon alpha 2b, 20 MU/m²/d i.v. 5 days per week x 4
weeks, followed by 10 MU/m² s.c. 3 days per week x 48 weeks 1 mL plus GMK was
administered s.c. on weeks 1, 2, 3, 4, 12, 24, and 36 (each dose contained 30 µg of
GM2 and 100 µg of QS21). GMK vaccine was started on day 1, while interferon alpha
2b was started after 5 weeks
• Group C: GMK was administered s.c. on weeks 1, 2, 3, 4, 12, 24, and 36 (each
dose contained 30 µg of GM2 and 100 µg of QS21)

Outcomes 1. Disease-free survival: GMK combined with interferon alpha 2b (arms A and B)
was associated with longer survival compared to participants who received GMK alone
2. Overall survival: No significant difference was observed between treatment arms
(data suitable for meta-analysis were not reported)
Subgroup analysis: not performed

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Kirkwood 2001a (Continued)

Notes Median follow-up: 24 months

Lymph node dissection: not reported
Participants with lymph node metastasis: 89%
Dose reduction/treatment discontinuation: 17 participants (16%) discontinued treat-
ment (12 because of toxicity, and 5 withdrew consent)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were assigned randomly”
bias) There was insufficient information about
the sequence generation process

Allocation concealment (selection bias) Low risk The trial used central allocation

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Kleeberg 2004

Methods Participants were randomised by 45 institutions in 13 countries within the frame of the
EORTC 18871 3-arm trial (comparing observation versus interferon alpha 2b versus
interferon gamma) and the DKG-80-1 4-arm trial (comparing observation versus inter-
feron alpha versus interferon gamma versus Iscador-M)
Accrual period: 1988 to 1996
Design: phase III RCT

Participants Number of participants: 830

EORTC 18871 3-arm trial (N = 423): observation N = 142; interferon alpha 2b N =
139; interferon gamma N = 142

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Kleeberg 2004 (Continued)

DKG-80-1 4-arm trial (N = 407): observation N = 102; interferon alpha 2b N = 101;

interferon gamma N = 102; Iscador-M N = 102
In order to ascertain interferon’s role in the adjuvant treatment of high-risk melanoma
participants, the results of these 2 trials were pooled together: Overall, there were 244
participants in the observation arm, 240 in the interferon alpha 2b arm, and 244 in the
interferon gamma arm
Participants randomised: 830
Participants evaluable: 793
Inclusion criteria of the trial
• age 14 to 80
• primary melanoma thick 3 mm or presence of lymph node metastasis regardless of
primary tumour thickness
• primary tumour resected with at least 2 cm surgical margin
Exclusion criteria of the trial
• not reported

Interventions • Interferon alpha 2b: 1 MU s.c. every other day for 1 year
• Interferon gamma: 0.2 mg s.c. every other day for 1 year
• Iscador-M: Treatment was started at “dose level 0”, and the dose was escalated
from 0.01 to 1.0 mg/ml, every other day, over 2 weeks. After 3 days without treatment,
injections were resumed for 14 doses (28 days) of 20 mg/ml followed by 7 days of no
treatment

Outcomes 1. Disease-free survival: There was no significant difference between interferon and
observation arm
2. Overall survival: There was no significant difference between interferon and
observation arm

Notes Median follow-up: not reported

Lymph node dissection: Clinically lymph node-positive participants received radical
lymph node dissection, while clinically node-negative participants were treated with
elective lymph node dissection or followed by observation based upon each institution’s
policy
Participants with lymph node metastasis: 58%
Dose reduction/treatment discontinuation: 11 participants (4.6%) treated with inter-
feron alpha 2b, 19 (7.8%) treated with interferon gamma, and 5 (4.9%) in the Iscador-
M arm due to toxicity
Quality of life: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “Patients were randomized”
bias) There was insufficient information about
the sequence generation process

Allocation concealment (selection bias) Low risk The trial used central allocation

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Kleeberg 2004 (Continued)

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

McMasters 2008

Methods The Sunbelt Melanoma Trial involved 79 centres across North America
Accrual period: 1997 to 2003
Design: phase III RCT

Participants Number of participants: 774

Protocol A: Participants with only 1 pathologically positive sentinel lymph node (SLN)
who underwent completion lymph node dissection (CLND) were randomised to obser-
vation (group A) versus high-dose interferon therapy (group B)
Protocol B: Histologically negative SLN were analysed by reverse transcription poly-
merase chain reaction (PCR); participants with PCR-positive SLN were randomised to
3 treatment arms: observation (group C), CLND (group D), or CLND plus interferon
(group E)
Participants randomised: 774
Participants evaluable: 774
Inclusion criteria of the trial
• age 18 to 70 years
• cutaneous melanomas > = 1 mm thick
Exclusion criteria of the trial
• evidence of regional or distant metastasis

Interventions Protocol A (participants with 1 positive sentinel lymph node submitted to CLND)
• Group A: observation
• Group B: interferon alpha 2b 20 MU/m² i.v. per day, 5 days per week × 4 weeks
followed by 10 MU/m² s.c. 3 times per week for 48 weeks
Protocol B (participants with histologically negative but PCR-positive SLN)
• Group C: observation

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McMasters 2008 (Continued)

• Group D: completion lymph node dissection (CLND)

• Group E: interferon alpha 2b 20 MU/m² i.v. per day, 5 days per week × 4 weeks
(1997 to 1999). Since 1999, this schedule was followed by 10 MU/m² s.c. 3 times per
week for 48 weeks

Outcomes 1. Disease-free survival: There was no significant difference between interferon and
observation arm in either protocols
2. Overall survival: There was no significant difference between interferon and
observation arm in either protocols
Subgroup analysis: A paper reporting a subgroup analysis from this trial investigated
the association between primary tumour ulceration and regional lymph node status,
showing that interferon treatment was associated with improved disease-free survival in
participants with ulcerated primaries and lymph node metastasis (McMasters 2010)

Notes Median follow-up: 64 months

Lymph node dissection: All participants underwent SLN biopsy; CLND was performed
according to the above reported criteria
Participants with lymph node metastasis: 18%
Dose reduction/treatment discontinuation: not reported
Quality of life: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk There was insufficient information about
bias) the sequence generation process

Allocation concealment (selection bias) Unclear risk There was insufficient information to per-
mit judgment

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Unclear risk There was insufficient reporting of attrition
All outcomes or exclusions to permit judgment

Selective reporting (reporting bias) Unclear risk There was insufficient information to per-
mit judgment

Other bias Low risk There was insufficient information to assess

whether an important risk of bias exists,
but we judged this study to be free of other
sources of bias

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Pehamberger 1998

Methods The Austrian Melanoma Cooperative Group (7 Institutions) conducted the study
Accrual period: 1990 to 1994
Design: phase III RCT

Participants Number of participants: 311

Interferon alpha 2a N = 154 (group A); observation N = 157 (group B)
Participants randomised: 311
Participants evaluable: 293
Inclusion criteria of the trial
• age 18 to 75 years
• Breslow thickness > 1.5 mm with negative lymph node (AJCC TNM stage II
participants)
Exclusion criteria of the trial
• evidence of distant, lymph node metastasis, or both
• secondary neoplasm

Interventions • Group A: interferon alpha 2a 3 MU x 7/week (3-week, route: s.c.) + 3 MU s.c. x

3/week (12 months, route: s.c.)
• Group B: observation

Outcomes 1. Disease-free survival: Interferon alpha 2a was found to provide a significant

survival advantage
2. Overall survival: not investigated
Subgroup analysis: No significant subgroup of enrolled participants had a benefit after
interferon treatment

Notes Median follow-up: 41 months

Lymph node dissection: Elective lymph node dissection was not performed
Participants with lymph node metastasis: 0%
Dose reduction/treatment discontinuation: A dose reduction was necessary in 8 treated
participants and a discontinuation of treatment in 12
Quality of life: not reported

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Quote: “patients were randomly assigned”
bias) There was insufficient information about
the sequence generation process

Allocation concealment (selection bias) Unclear risk There was insufficient information to per-
mit judgment

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

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Pehamberger 1998 (Continued)

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias) Low risk Missing outcome data were balanced in
All outcomes numbers across intervention groups, with
similar reasons for missing data across
groups

Selective reporting (reporting bias) Low risk The study protocol was not available, but
it is clear that the published reports include
all expected outcomes

Other bias Low risk The study appeared to be free of other

sources of bias

Rusciani 1997

Methods The study was conducted by the Catholic University and Sapienza University, Rome,
Italy
Accrual period: not available
Design: phase III RCT

Participants Number of participants: 154

Interferon alpha 2b N = 84 (group A); observation N = 70 (group B)
Participants randomised: 154
Participants evaluable: 154
Inclusion criteria of the trial
• participants with cutaneous melanoma and clinically negative lymph node
Exclusion criteria of the trial
• not reported

Interventions • Group A: interferon alpha 2b 3 MU × 3/week (3-week, route: i.m.) for cycles of 6
months with 1-month interval between cycles for 3 years
• Group B: observation

Outcomes The crude incidence of recurrence was lower for participants treated with interferon
alpha than participants enrolled in the control arm
The analysis were not performed following a methodology suitable to investigate survival

Notes Median follow-up: not reported

Lymph node dissection: not performed
Participants with lymph node metastasis: 0%
Dose reduction/treatment discontinuation: Treatment suspension or discontinuation
was never required because of adverse events
Quality of life: not reported

Risk of bias

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Rusciani 1997 (Continued)

Bias Authors’ judgement Support for judgement

Random sequence generation (selection High risk Quote: “The authors have started a ran-
bias) domized clinical trial”, “concomitant pa-
tients”
Comment: We contacted the authors of the
study by telephone, and they confirmed the
randomised design of the study
There was no information about the se-
quence generation process

Allocation concealment (selection bias) High risk There was no information about allocation
concealment

Blinding of participants and personnel Low risk There was no blinding, but we judged that
(performance bias) lack of blinding was not likely to influence
All outcomes the outcome

Blinding of outcome assessment (detection Low risk There was no blinding, but we judged that
bias) lack of blinding was not likely to influence
All outcomes the outcome

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk There was insufficient reporting of attri-
tion/exclusions to permit judgement of
’low risk’ or ’high risk’ (e.g. number ran-
domised not stated; no reasons for missing
data provided)

Selective reporting (reporting bias)
High risk Outcomes of interest in the review were re-
ported incompletely, so we could not enter
them in a meta-analysis. The study report
fails to include results for disease-free sur-
vival, overall survival, or both, which would
be expected to have been reported for such
a study

Other bias Low risk The study appeared to be free of other

sources of bias

Characteristics of excluded studies [ordered by study ID]

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Study Reason for exclusion

Anaya 2008 This was a non-randomised study

Chiarion-Sileni 2011 As this trial compared 2 different schedules/dosages of adjuvant interferon alpha (i.e. intensified dose of
interferon alpha versus standard high dose), it was not suitable for investigating whether or not interferon
is superior to any comparator other than interferon for the adjuvant treatment of high-risk melanoma
participants

Dillman 2003 Participants enrolled in this study received interferon gamma and not interferon alpha, which is the drug
under investigation in this review

Grob 2010 As this trial compared 2 different schedules and types of interferon (36 months of pegylated interferon versus
18 months of low-dose interferon), it was not suitable for investigating whether or not interferon is superior
to any comparator other than interferon for the adjuvant treatment of high-risk melanoma participants

Hauschild 2003 This study randomised participants to low-dose interferon in a combination regimen with low-dose inter-
leukin-2 or to observation. The presence of interleukin-2 (an active drug in metastatic melanoma) in the
treatment schedule might affect interferon efficacy, which precluded inclusion of this trial

Hauschild 2009 As this trial compared 2 different schedules/dosages of adjuvant interferon alpha (i.e. low-dose interferon
alpha 2b with or without a modified high-dose interferon alpha 2b induction phase), it was not suitable for
investigating whether or not interferon is superior to any comparator other than interferon for the adjuvant
treatment of high-risk melanoma participants

Hauschild 2010 As this trial compared 2 different schedules/dosages of adjuvant interferon alpha (i.e. low-dose interferon
alpha 2a for 18 versus 60 months), it was not suitable for investigating whether or not interferon is superior
to any comparator other than interferon for the adjuvant treatment of high-risk melanoma participants

Kerin 1995 As this trial compared interferon combined with dacarbazine versus observation, it was not suitable for
investigating whether or not interferon is superior to any comparator other than interferon for the adjuvant
treatment of high-risk melanoma participants

Kim 2009 This was a 2-arm randomised trial comparing biochemotherapy (including interferon) versus interferon in
high-risk melanoma participants. As interferon was included in both treatment arms, this trial was not suitable
for inclusion in this review

Kokoschka 1990 The randomisation of the trial was unclear. Even though the authors mentioned that participants were
randomly selected to receive interferon alpha therapy, there was no mention of a corresponding randomised
control arm

Mao 2011 This phase II randomised study enrolled participants with acral melanoma and compared different interferon
schedules (i.e. 1 month versus 1 year high-dose interferon adjuvant treatment), so it did not meet the inclusion
criteria of this review

Meyskens 1995 Participants enrolled in this study received interferon gamma and not interferon alpha, which is the drug
under investigation in this review

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(Continued)

Mitchell 2007 Participants of this study were randomly assigned to receive low-dose interferon alpha plus specific im-
munotherapy with allogeneic melanoma lysates or high-dose interferon alpha. As interferon was included in
both treatment arms, this trial was not suitable for investigating whether or not interferon is superior to any
comparator other than interferon for the adjuvant treatment of high-risk melanoma participants

Mohr 2008 As this trial compared 2 different schedules/dosages of adjuvant interferon alpha (i.e. intensified dose of
interferon alpha versus standard high dose), it was not suitable for investigating whether or not interferon
is superior to any comparator other than interferon for the adjuvant treatment of high-risk melanoma
participants

Pectasides 2009 As this trial compared 2 different schedules of adjuvant interferon alpha (1 month versus 1 year), it was not
suitable for investigating whether or not interferon is superior to any comparator other than interferon for
the adjuvant treatment of high-risk melanoma participants

Richtig 2005 Participants with AJCC stage II melanoma were randomly assigned to receive interferon alpha at a dosage
of 3 megaunits 3 times each week for 2 years, plus isotretinoin at a dose of 20 mg for participants < or = 73
kg, 30 mg for participants greater than 73 kg, versus interferon alpha at the same dosage plus placebo. As
interferon alpha was scheduled in both arms, it was not eligible for inclusion

Rusciani 2007 This was a non-randomised study

Characteristics of ongoing studies [ordered by study ID]

ECOG E1609

Trial name or title A Phase III Randomized Study of Adjuvant Ipilimumab Anti-CTLA4 Therapy Versus High-Dose Interferon
Alpha-2b for Resected High-Risk Melanoma (clinicaltrial.gov identifier: NCT01274338)

Methods This is a phase III randomised study

Participants • High-risk stage III or stage IV melanoma that has been removed by surgery

Interventions • Experimental: Participants receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every
21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity. Beginning on
week 24, participants receive maintenance ipilimumab IV over 90 minutes on day 1. Treatment repeats
every 90 days for a maximum of 4 courses in the absence of disease progression or unacceptable toxicity
• Active comparator: Participants receive high-dose recombinant interferon alpha 2b IV on days 1 to 5,
8 to 12, 15 to 19, and 22 to 26 in the absence of disease progression or unacceptable toxicity. Participants
then receive maintenance high-dose recombinant interferon alpha 2b subcutaneously on days 1, 3, and 5.
Treatment repeats every week for 48 weeks in the absence of disease progression or unacceptable toxicity

Outcomes Primary outcomes of the trial

1. Recurrence-free survival
2. Overall survival
Secondary outcomes of the trial
1. Toxicity

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ECOG E1609 (Continued)

2. Quality of life

Starting date May 2011

Contact information Principal Investigator: Ahmad Tarhini, Eastern Cooperative Oncology Group

Notes Expected primary completion date: May 2018

EORTC 18081

Trial name or title Adjuvant Pegylated-Interferon-alpha2b (SylatronTM) for 2 Years Versus Observation in Patients With an
Ulcerated Primary Cutaneous Melanoma With T(2-4)bN0M0: a Randomized Phase III Trial of the EORTC
Melanoma Group (clinicaltrial.gov identifier: NCT01502696)

Methods This is a phase III randomised study

Participants • Patients with an ulcerated melanoma with Breslow > 1 mm (T2b, T3b, T4b), lymph node-negative
(N0), and no distant metastasis (M0)

Interventions • Experimental: PEG IFN alpha 2b (3 µg/kg weekly injections)

• No intervention: observation

Outcomes Primary outcomes of the trial

1. Relapse-free survival
Secondary outcomes of the trial
1. Toxicity
2. Overall survival
3. Distant metastases-free survival
4. Quality of life

Starting date October 2012

Contact information Alexander Eggermont, Institut Gustave Roussy, Paris, France

Notes Expected primary completion date: April 2020

NCT01782508

Trial name or title A Phase II Randomized Study of Imatinib Versus High Dose Interferon as Adjuvant Therapy in KIT-mutated
Patients With Resected Melanoma

Methods This is a phase II randomised study

Participants • Melanoma patients who had lymph node metastasis removed

Interventions • Experimental: Participants will take 400 mg imatinib once daily for 1 year
• Active comparator: Participants will receive interferon 1500 wiu/m² d1-5 for 4 weeks followed by 900

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NCT01782508 (Continued)

wiu IH 3 days/week for 11 months

Outcomes Primary outcomes of the trial

1. Relapse-free survival
Secondary outcomes of the trial
1. Overall survival

Starting date August 2012

Contact information Jun Guo, Peking University Cancer Hospital

Notes Expected primary completion date: December 2014

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DATA AND ANALYSES

Comparison 1. Interferon alpha versus any other comparator

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Disease-free survival (DFS) 17 Hazard Ratio (Fixed, 95% CI) 0.83 [0.78, 0.87]
2 Overall Survival (OS) 15 Hazard Ratio (Fixed, 95% CI) 0.91 [0.85, 0.97]

Analysis 1.1. Comparison 1 Interferon alpha versus any other comparator, Outcome 1 Disease-free survival
(DFS).

Review: Interferon alpha for the adjuvant treatment of cutaneous melanoma

Comparison: 1 Interferon alpha versus any other comparator

Outcome: 1 Disease-free survival (DFS)

Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio
(SE) IV,Fixed,95% CI IV,Fixed,95% CI

Agarwala 2011 -0.09 (0.08) 12.8 % 0.91 [ 0.78, 1.07 ]

Cameron 2001 -0.228 (0.221) 1.7 % 0.80 [ 0.52, 1.23 ]

Cascinelli 2001 -0.133 (0.195) 2.2 % 0.88 [ 0.60, 1.28 ]

Creagan 1995 -0.274 (0.158) 3.3 % 0.76 [ 0.56, 1.04 ]

Eggermont 2005 -0.128 (0.08) 12.8 % 0.88 [ 0.75, 1.03 ]

Eggermont 2008 -0.175 (0.075) 14.6 % 0.84 [ 0.72, 0.97 ]

Garbe 2008 -0.371 (0.156) 3.4 % 0.69 [ 0.51, 0.94 ]

Grob 1998 -0.301 (0.143) 4.0 % 0.74 [ 0.56, 0.98 ]

Hancock 2004 -0.094 (0.098) 8.5 % 0.91 [ 0.75, 1.10 ]

Hansson 2011 -0.223 (0.091) 9.9 % 0.80 [ 0.67, 0.96 ]

Kirkwood 1996 -0.407 (0.144) 4.0 % 0.67 [ 0.50, 0.88 ]

Kirkwood 2000 -0.211 (0.111) 6.7 % 0.81 [ 0.65, 1.01 ]

Kirkwood 2001 -0.399 (0.118) 5.9 % 0.67 [ 0.53, 0.85 ]

Kirkwood 2001a -0.528 (0.306) 0.9 % 0.59 [ 0.32, 1.07 ]

Kleeberg 2004 0.049 (0.111) 6.7 % 1.05 [ 0.84, 1.31 ]

0.5 0.7 1 1.5 2

Favours IFN Favours control
(Continued . . . )

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 (. . .
Continued)
Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio
(SE) IV,Fixed,95% CI IV,Fixed,95% CI
McMasters 2008 -0.198 (0.278) 1.1 % 0.82 [ 0.48, 1.41 ]

Pehamberger 1998 -0.491 (0.211) 1.8 % 0.61 [ 0.40, 0.93 ]

Total (95% CI) 100.0 % 0.83 [ 0.78, 0.87 ]

Heterogeneity: Chi2 = 18.98, df = 16 (P = 0.27); I2 =16%
Test for overall effect: Z = 6.63 (P < 0.00001)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours IFN Favours control

Analysis 1.2. Comparison 1 Interferon alpha versus any other comparator, Outcome 2 Overall Survival
(OS).

Review: Interferon alpha for the adjuvant treatment of cutaneous melanoma

Comparison: 1 Interferon alpha versus any other comparator

Outcome: 2 Overall Survival (OS)

Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio
(SE) IV,Fixed,95% CI IV,Fixed,95% CI

Agarwala 2011 0.01 (0.11) 8.9 % 1.01 [ 0.81, 1.25 ]

Cameron 2001 -0.151 (0.231) 2.0 % 0.86 [ 0.55, 1.35 ]

Cascinelli 2001 -0.051 (0.117) 7.9 % 0.95 [ 0.76, 1.20 ]

Creagan 1995 -0.105 (0.171) 3.7 % 0.90 [ 0.64, 1.26 ]

Eggermont 2005 -0.094 (0.089) 13.6 % 0.91 [ 0.76, 1.08 ]

Eggermont 2008 0.001 (0.09) 13.3 % 1.00 [ 0.84, 1.19 ]

Garbe 2008 -0.478 (0.171) 3.7 % 0.62 [ 0.44, 0.87 ]

Grob 1998 -0.357 (0.172) 3.6 % 0.70 [ 0.50, 0.98 ]

Hancock 2004 -0.062 (0.116) 8.0 % 0.94 [ 0.75, 1.18 ]

Hansson 2011 -0.094 (0.103) 10.2 % 0.91 [ 0.74, 1.11 ]

Kirkwood 1996 -0.315 (0.154) 4.5 % 0.73 [ 0.54, 0.99 ]

0.5 0.7 1 1.5 2

Favours IFN Favours control
(Continued . . . )

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Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 (. . .
Continued)
Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio
(SE) IV,Fixed,95% CI IV,Fixed,95% CI
Kirkwood 2000 -0.021 (0.122) 7.2 % 0.98 [ 0.77, 1.24 ]

Kirkwood 2001 -0.328 (0.162) 4.1 % 0.72 [ 0.52, 0.99 ]

Kleeberg 2004 -0.021 (0.12) 7.5 % 0.98 [ 0.77, 1.24 ]

McMasters 2008 0.068 (0.256) 1.6 % 1.07 [ 0.65, 1.77 ]

Total (95% CI) 100.0 % 0.91 [ 0.85, 0.97 ]

Heterogeneity: Chi2 = 14.93, df = 14 (P = 0.38); I2 =6%
Test for overall effect: Z = 2.97 (P = 0.0029)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours IFN Favours control

ADDITIONAL TABLES
Table 1. Glossary of terms

Medical term Explanation

Adjuvant treatment Any medical oncology therapy used after surgery to kill microscopic tumour residues not removed by
the surgeon

AJCC TNM stages I-IV Stage I and II = primary melanomas with negative regional lymph nodes
Stage III = regional lymph node melanoma metastasis from known or unknown primary tumours
Stage IV = melanoma metastasis at distant site (e.g. lung, liver, brain)

Apoptosis Apoptosis is a genetically determined process of programmed cell death that may occur in cells.
Apoptosis is a normal physiological process eliminating DNA-damaged, superfluous, or unwanted
cells and when halted may result in uncontrolled cell growth and tumour formation

Angiogenesis Development of new blood vessels. It may occur in the healthy body for healing of wounds and
restoring blood flow to tissues after injury, or in tumours, where it promotes the spread of cancer cells
through new blood vessels

Lymphadenectomy This surgical operation aims to remove the lymph nodes of 1 or more of the 3 main fields (neck, axilla,
groin) where metastatic melanoma cells are present

Metastasis The spread of a malignant tumour from its original site to any part of the body (such as lymph nodes,
lungs, liver, brain, bones, and so on)

Neoadjuvant treatment Any medical oncology therapy used before surgery to reduce the tumour bulk

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 63

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Table 1. Glossary of terms (Continued)

Pegylated interferon The addition of polyethylene glycol to the interferon molecule to improve the effectiveness of the drug

Randomised controlled trial This is a particular design of study, in which participants are randomly assigned to different treatments.
A randomised controlled trial provides the highest evidence for the use, or not, of a diagnostic or
therapeutic intervention

Sentinel node biopsy Surgical procedure to find the first lymph node that drains the skin area of the primary melanoma.
The pathological evaluation of the sentinel node allows definition of the status of the lymphatic field
when no clinically evident regional lymph node metastasis is present

TNM classification
This is the international classification of tumour spread issued by the American Joint Committee on
Cancer (AJCC): “T” refers to the size of a tumour, “N” to the presence and extent of lymph node
metastasis, and “M” indicates whether or not distant metastatic disease (that is, to lungs, liver, brain,
bones) is present
E.g. AJCC stage II (T2-4N0M0): T2-4 refers to the size and extent of the primary tumour; N0 refers
to no regional lymph node involvement; M0 refers to no metastases
AJCC stage III (TanyN+M0): Tany refers to any size and extent of the primary tumour, including
thin (< 1.00 mm) and thick melanomas (> 4.00 mm); N+ refers to any number of positive regional
lymph nodes

Grades of toxicity Grade 0 = no adverse event or within normal limits

Grade 1 = mild adverse event
Grade 2 = moderate adverse event
Grade 3 = severe and undesirable adverse event
Grade 4 = life-threatening or disabling adverse event

Table 2. Included studies

Study Design Sample size Setting Participants (AJCC Intervention (inter- Outcome (P value)
TNM stage) feron schedule)

Creagan 1995 Phase III RCT 264 Adjuvant II-III IFNa(2a): 20 MU/ DFS: not significant
(T2-4N0M0/ sqm x 3/week for 4 OS: not significant
TanyN+M0) months (route: i.m.)

Kirkwood 1996 Phase III RCT 287 Adjuvant II-III IFNa(2b): 20 MU/ DFS: 0.0013
(T4N0M0/ sqm x 5/week (1 OS: 0.015
TanyN+M0) month, route: i.v.)
+ 10 MU/sqm x
3/week (48 weeks,
route: s.c.)

Rusciani 1997 Phase III RCT 154 Adjuvant I-II IFNa(2a): 3 MU x 3/ DFS: not reported
(TanyN0M0) week (3 weeks, route: OS: not reported
i.m.) x 6 months, fol-
lowed by a month
with no treatment x

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 64

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Included studies (Continued)

3 years

Pehamberger Phase III RCT 311 Adjuvant II IFNa(2a): 3 MU x 7/ DFS: 0.02

1998 (T2-4N0M0) week (3 weeks, route: OS: not evaluated
s.c.) + 3 MU sc x
3/week (12 months,
route: s.c.)

Grob 1998 Phase III RCT 499 Adjuvant II IFNa(2a): 3 MU x DFS: 0.033
(T2-4N0M0) 3/week (18 months, OS: 0.046
route: s.c.)

Kirkwood 2000 Phase III RCT 642 Adjuvant II-III IFNa(2b) (high): 20 DFS (high): 0.03
(T4N0M0/ MU/sqm x 5/week DFS (low): not sig-
TanyN+M0) (1 month, route: i. nificant
v.) + 10 MU/sqm OS: not significant
x 2/week (48 weeks,
route: s.c.). IFNa(2b)
(low): 3 MU x 2/
week (2 years, route:
s.c.)

Cameron 2001 Phase III RCT 96 Adjuvant II-III IFNa(2b): 3 MU x DFS: not significant
(T3-4N0M0/ 3/week (6 months, OS: not significant
TanyN+M0) route: s.c.)

Kirkwood 2001 Phase III RCT 880 Adjuvant II-III IFNa(2b): 20 MU/ DFS: 0.0027
(T4N0M0/ sqm x 5/week (1 OS: 0.0147
TanyN+M0) month, route: i.v.)
+ 10 MU/sqm x
2/week (48 weeks,
route: s.c.)

Cascinelli 2001 Phase III RCT 444 III IFNa(2a): 3 MU x DFS: not significant
(TanyN+M0) 3/week (36 months, OS: not significant
route: s.c.)

Kirkwood 2001 Phase II RCT 107 Adjuvant II-III-IV IFNa(2b) (d1): IFNa DFS (d1): 0.016
(stage IV: resectable (from day 1) 20 DFS (d28): 0.03
metastatic disease) MU/sqm x 5/week OS: not significant
(1 month, route: i.
v.) + 10 MU/sqm
x 3/week (48 weeks,
route: s.c.). IFNa(2b)
(d28): IFNa as above
(from day 28)

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 65

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Included studies (Continued)

Hancock 2004 Phase III RCT 674 Adjuvant II-III IFNa(2a): 3 MU x 3/ DFS: not significant
(T4N0M0/ week (2 years, route: OS: not significant
TanyN+M0) s.c.)

Kleeberg 2004 Phase III RCT 830 Adjuvant II-III IFNa(2b): 1 MU ev- DFS: not significant
(T3-4N0M0/ ery other day (12 OS: not significant
TanyN+M0) months, route: s.c.)

Eggermont 2005 Phase III RCT 1388 Adjuvant II-III IFNa(2b) (1 year): DFS: not significant
(T4N0M0/ 10 MU x 5/week (4 OS: not significant
TanyN+M0) weeks, route: s.c.) +
10 MU x 3/week (12
months, route: s.c.)
IFNa(2b) (2 years):
10 MU x 5/week (4
weeks, route: s.c.) +
5 MU x 3/week (24
months, route: s.c.)

Garbe 2008 Phase III RCT 444 Adjuvant III IFNa(2a): 3 MU x 3/ DFS: 0.018
(TanyN+M0) week (2 years, route: OS: 0.005
s.c.)

Eggermont 2008 Phase III RCT 1256 Adjuvant III Pegylated IFNa(2b) DFS: 0.02
(TanyN+M0) : 6 ug/Kg/week (8 OS: not significant
weeks, route: s.c.) +
3 ug/Kg/w (5 years,
route: s.c.)

McMasters 2008 Phase III RCT 774 Adjuvant II-III IFNa(2b): 20 MU/ DFS: not significant
(T2-4N0M0/ sqm x 5/week (1 OS: not significant
TanyM0)* month, route: i.v.)
+ 10 MU/sqm x
3/week (48 weeks,
route: s.c.)

Hansson 2011 Phase III RCT 855 Adjuvant II-III IFNa (2b) (1 year): DFS: 0.034
(T4N0M0/ 10 MU x 5/week (4 OS: not significant
TanyN+M0) weeks, route: s.c.) +
10 MU x 3/week (12
months, route: s.c.)
IFNa (2b) (2 years):
10 MU x 5/week (4
weeks, route: s.c.) +
10 MU x 3/week (24
months, route: s.c.)

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Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Table 2. Included studies (Continued)

Agarwala 2011 Phase III RCT 1150 Adjuvant II-III IFNa(2b): DFS: not significant
(T3-4N0M0/ 20MU/sqm x 5/week OS: not significant
TanyN1a-N2aM0) (1 month, route: i.v.)
*Negative sentinel lymph node after standard pathological evaluation (H&E and immunohistochemistry) were tested with polymerase
chain reaction (PCR) analysis

Table 3. Additional analyses: disease-free survival (DFS)

Trial feature RCT HR (95% CI) # Z-test P value I² statistic Q-test P value Type of analysis References

Interferon 8* 0.80 (0.74 to 0. < 0.0001 14% 0.32 Subgroup meta- 1to8

dose: high 87) analysis

Interferon 8* 0.85 (0.77 to 0. 0.001 25% 0.23 Subgroup meta- 8to15

dose: low 94) analysis

16,17
Interferon 2 0.84 (0.75 to 0. 0.005 0% 0.43 Subgroup meta-
dose: interme- 95) analysis
diate

Interferon 17 Q-value = 0.99 - 0% 0.61 Heterogeneity 1to17

dose

TNM stage: II 2 0.70 (0.55 to 0. 0.002 0% 0.46 Subgroup meta- 12,15

88) analysis

TNM stage: 5 0.85 (0.77 to 0. 0.001 0% 0.61 Subgroup meta- 1,3,6,10,11

III 94) analysis

TNM stage: 10 0.83 (0.77 to 0. < 0.0001 32% 0.15 Subgroup meta- 2,4,5,7to9,13,14,16,17

II-III 89) analysis

1to17
TNM stage 17 Q-value = 2.23 - 10% 0.33 Heterogeneity

Publication 17 Slope = 0.01 (- 0.06 - - Metaregression 1to17

year 0.0004 to 0.02)

Treatment du- 17 Slope = 0.0001 0.09 - - Metaregression 1to17

ration (-0.003 to 0.
003)

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Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Statistics : Z-test: tests the significance of meta-analysis summary effect;I² statistic: measures between-study heterogeneity in meta-
analysis; Q-test: tests the significance of heterogeneity; Q-value: Q-test statistic; slope: coefficient of metaregression model
Abbreviations : interferon: interferon alpha; RCT: randomised controlled trial; HR: hazard ratio (from meta-analysis); CI: hazard ratio
confidence interval
References : 1: Agarwala 2011; 2: Creagan 1995; 3: Eggermont 2008; 4: Kirkwood 1996; 5: Kirkwood 2001; 6: McMasters 2008; 7:
Kirkwood 2001a; 8: Kirkwood 2000; 9: Cameron 2001; 10: Cascinelli 2001; 11: Garbe 2008; 12: Grob 2010; 13: Hancock 2004;
14: Kleeberg 2004; 15: Pehamberger 1998; 16: Eggermont 2005; 17: Hansson 2011
Notes : *: The starred values indicate that one study (Kirkwood 2000) is represented twice (in both high- and low-dose interferon
groups) because this trial had three arms: observation, high-dose interferon, and low-dose interferon. #: The third column displays
hazard ratios if not otherwise specified

Table 4. Additional analyses: overall survival (OS)

Feature RCT HR (95% CI) # Z-test P value I² statistic Q-test P value Type of analysis References

1to7
Interferon 7* 0.93 (0.84 to 1. 0.16 11% 0.34 Subgroup meta-
dose: high 03) analysis

Interferon 7* 0.88 (0.79 to 0. 0.02 23% 0.25 Subgroup meta- 7to13

dose: low 98) analysis

Interferon 2 0.91 (0.80 to 1. 0.16 0% 1.00 Subgroup meta- 14,15

dose: interme- 04) analysis

diate

Interferon 15 Q-value = 0.53 - 0% 0.76 Heterogeneity 1to15

dose

TNM stage: II 1 0.70 (0.50 to 0. - - - N/A 11

98)

TNM stage: 5 0.95 (0.85 to 1. 0.32 43% 0.13 Subgroup meta- 1,3,6,9,10

III 05) analysis

TNM stage: 9 0.90 (0.83 to 0. 0.01 0% 0.77 Subgroup meta- 2,4,5,7,8,12to15

II-III 98) analysis

TNM stage 15 Q-value = 3.11 - 36% 0.21 Heterogeneity 1to15

Publication 15 Slope = 0.01 (- 0.16 - - Metaregression 1to15

year 0.004 to 0.023)

Treatment du- 15 Slope = 0.001 (- 0.52 - - Metaregression 1to15

ration 0.002 to 0.005)

Statistics : Z-test: tests the significance of meta-analysis summary effect;I² statistic: measures between-study heterogeneity in meta-
analysis; Q-test: tests the significance of heterogeneity; Q-value: Q-test statistic; slope: coefficient of metaregression model
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 68
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Abbreviations : interferon: interferon alpha; RCT: randomised controlled trial; HR: hazard ratio (from meta-analysis); CI: hazard ratio
confidence interval; N/A: not applicable
References : 1: Agarwala 2011; 2: Creagan 1995; 3: Eggermont 2008; 4: Kirkwood 1996; 5: Kirkwood 2001; 6: McMasters 2008; 7:
Kirkwood 2000; 8: Cameron 2001; 9: Cascinelli 2001; 10: Garbe 2008; 11: Grob 2010; 12: Hancock 2004; 13: Kleeberg 2004; 14:
Eggermont 2005; 15: Hansson 2011
Notes : *: The starred values indicate that one study (Kirkwood 2000) is represented twice (in both high- and low-dose interferon
groups) because this trial had three arms: observation, high-dose interferon, and low-dose interferon. #: The third column displays
hazard ratios if not otherwise specified

Table 5. Grade 3 to 4 adverse events after treatment with adjuvant interferon alpha

Arm Fever Fatigue Myalgia Arthralgia Anorexia Dizziness Headache Mood

Study

Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade
3 4 3 4 3 4 3 4 3 4 3 4 3 4 3 4
(%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)

IFN <1 0 NR NR NR NR NR NR NR NR 0 NR 1 NR <1 <1

Grob
1998 Ob- NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR
ser-
va-
tion

NR NR 23 1 16 1 NR NR NR NR NR NR NR NR 8 1
Kirk-
High-
wood
dose
2000 IFN

NR NR 3 0 8 1 NR NR NR NR NR NR NR NR 2 0
Low-
dose
IFN

Ob- NR NR 0 0 0 0 NR NR NR NR NR NR NR NR 0 0
ser-
va-
tion

IFN NR NR 20.6 0.3 3.8 0 NR NR NR NR NR NR NR NR 8.6 1.3

Kirk-
wood
2001 GSK NR NR 1.2 0 0.5 0 NR NR NR NR NR NR NR NR 0.5 0.2

IFN 1 0 6.7 0 NR NR NR NR NR NR NR NR NR NR 3.1 0

Han-
cock
2004

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Table 5. Grade 3 to 4 adverse events after treatment with adjuvant interferon alpha (Continued)

Ob- 0 0 1.3 0 NR NR NR NR NR NR NR NR NR NR 1.6 0

ser-
va-
tion

Eg- 13- 6 1 14 1 7 1 6 1 6 1 4 1 5 1 10 2
ger- month
mont IFN
2005 25- 8 1 12 1 2 1 2 1 6 1 4 1 5 1 9 1
month
IFN

Ob- 0 0 2 0 2 0 2 1 1 0 2 1 2 0 2 1
ser-
va-
tion

IFN 0 0 NR NR NR NR NR NR NR NR NR NR NR NR 1.6 0.8

Garbe
2008 IFN 0 0 NR NR NR NR NR NR NR NR NR NR NR NR 1.6 0
+
DTIC

Ob- NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR NR
ser-
va-
tion

Eg- Peg- 4 1 15 1 4 1 NR NR NR NR NR NR 4 1 6 1
ger- IFN
mont
Ob- 0 0 1 0 1 0 NR NR NR NR NR NR 0 0 1 1
2008 ser-
va-
tion

13- 1.1 0.4 9.8 NR 5.3 NR 2.8 NR 3.5 NA NR NR 3.5 NR 4.9 1.1
Hans-
month
son
IFN
2011
25- 1 0 11.2 NR 4.9 NR 4.6 NR 3.5 NA NR NR 3.1 NR 2.4 0
month
IFN

Ob- 0.4 0 1.8 NR 1.1 NR 1.4 NR 0 NA NR NR 0.4 NR 0.4 0

ser-
va-
tion

NR: not reported

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 70

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Not available for Creagan 1995 (grades 3 and 4 not reported), Kirkwood 1996 (adverse events grouped as “constitutional symptoms”),
Pehamberger 1998 (grades 3 and 4 not reported), Cameron 2001, Cascinelli 2001, Kirkwood 2001 (E2696), Kleeberg 2004, McMaster
2008, Agarwala 2011

APPENDICES

Appendix 1. CENTRAL (Cochrane Library) search strategy

#1 (melanoma*)
#2 (interferon*) or (ifn alpha) or (ifn alfa)
#3 MeSH descriptor Interferons explode all trees
#4 MeSH descriptor Interferon-alpha explode all trees
#5 MeSH descriptor Melanoma explode all trees
#6 (#1 OR #5)
#7 (#2 OR #3 OR #4)
#8 (#6 AND #7)

Appendix 2. MEDLINE (OVID) search strategy

1. randomized controlled trial.pt.
2. controlled clinical trial.pt.
3. randomized.ab.
4. placebo.ab.
5. clinical trials as topic.sh.
6. randomly.ab.
7. trial.ti.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. (animals not (human and animals)).sh.
10. 8 not 9
11. exp Melanoma/
12. melanoma$.mp.
13. 11 or 12
14. interferon$.mp.
15. exp Interferons/ or exp Interferon-alpha/
16. (interferon alpha or interferon alfa).mp.
17. 14 or 15 or 16
18. 10 and 13 and 17

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 71

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 3. EMBASE (OVID) search strategy
1. random$.mp.
2. factorial$.mp.
3. (crossover$ or cross-over$).mp.
4. placebo$.mp. or PLACEBO/
5. (doubl$ adj blind$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer,
drug manufacturer]
6. (singl$ adj blind$).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer,
drug manufacturer]
7. (assign$ or allocat$).mp.
8. volunteer$.mp. or VOLUNTEER/
9. Crossover Procedure/
10. Double Blind Procedure/
11. Randomized Controlled Trial/
12. Single Blind Procedure/
13. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12
14. exp MELANOMA/
15. melanoma$.mp.
16. 14 or 15
17. interferon$.mp.
18. (interferon alpha or interferon alfa).mp.
19. exp INTERFERON/
20. exp alpha interferon/
21. 17 or 18 or 19 or 20
22. 13 and 16 and 21

Appendix 4. AMED (OVID) search strategy

1. randomized controlled trial$/
2. random allocation/
3. double blind method/
4. single blind method.mp.
5. exp Clinical trials/
6. (clin$ adj25 trial$).mp. [mp=abstract, heading words, title]
7. ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$ or dummy)).mp. [mp=abstract, heading words, title]
8. (placebo$ or random$).mp. [mp=abstract, heading words, title]
9. research design/ or clinical trials/ or comparative study/ or double blind method/ or random allocation/
10. prospective studies.mp.
11. cross over studies.mp.
12. Follow up studies/
13. control$.mp.
14. (multicent$ or multi-cent$).mp. [mp=abstract, heading words, title]
15. ((stud or design$) adj25 (factorial or prospective or intervention or crossver or cross-over or quasi-experiment$)).mp. [mp=abstract,
heading words, title]
16. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15
17. exp Melanoma/
18. melanoma$.mp. [mp=abstract, heading words, title]
19. 17 or 18
20. exp Interferons/
21. interferon$.mp. [mp=abstract, heading words, title]
22. 20 or 21
23. 16 and 19 and 22
Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 72
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Appendix 5. LILACS search strategy
melanoma$ and (interferon$ or ifn$)

WHAT’S NEW
Last assessed as up-to-date: 22 August 2012.

Date Event Description

12 October 2015 Review declared as stable A search in September 2015 found no relevant new results. Our Co-ordinating Editor
confirmed that there is currently no new data of relevance. Thus, this review has
been marked stable because an update has not been considered necessary for two
successive years. Our Trials Search Co-ordinator will run a new search in September
2016 to re-assess whether an update is needed

HISTORY
Protocol first published: Issue 1, 2011
Review first published: Issue 6, 2013

Date Event Description

7 October 2015 Amended Author information (affiliation) updated.

2 October 2014 Amended Although there were 3 ongoing studies listed in the last published review, a search of MEDLINE
and Embase in 2014 found some relevant results, and this is a rapidly moving field, this review has
currently been deemed not in need of an update because the review team assessed the aforementioned
search results and found that only 1 trial (Eggermont AM, Suciu S, Testori A, Santinami M, Kruit
WH, Marsden J, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant
therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. Journal
of Clinical Oncology 2012;30(31):3810-8. (DOI: 10.1200/JCO.2011.41.3799)) would be eligible
for the update. However, the review authors deemed that the data from this article were just an update
of a trial that they had already included in the review (Eggermont 2008), with the findings being
virtually identical to the original findings. Thus, an update has not been considered necessary at this
time. Our Trials Search Co-ordinator will run a new search towards the end of 2015 to re-assess
whether an update is needed

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 73

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
CONTRIBUTIONS OF AUTHORS
SM was the contact person for the editorial base, co-ordinated the contributions from the co-authors, analysed the data, and wrote the
final draft of the review.
ML and SP contributed to the methods section of the protocol and inputted the data into RevMan.
PP checked the protocol for readability, clarity, and for relevance to consumers.
SM and VCS are the guarantors of the final version of the review.

DECLARATIONS OF INTEREST
Sandro Pasquali, Marko B Lens, Pierluigi Pilati, and Simone Mocellin have all declared they have no conflicts of interest.
Vanna Chiarion-Sileni was reimbursed for consulting activity as a melanoma expert on advisory boards for GSK, Roche, BMS, and SMD.
This was always done with the approval of her institution and outside her work time. She received compensation for advisory board
participation from Merck, Roche Genentech, Bristol-Meyers Squibb, GlaxoSmithKline MSD for the drugs ipilimumab, dabrafenib,
vemurafenib, trametinib, and anti-Pd1. She was the medical leader of the following excluded study:
Chiarion-Sileni V, Guida M, Romanini A, Ridolfi R, Mandala M, Del Bianco P, et al. Intensified high-dose intravenous interferon
alpha 2b (IFNa2b) for adjuvant treatment of stage III melanoma: A randomized phase III Italian Melanoma Intergroup(IMI) trial
[ISRCTN75125874]. [Abstract 8506] ASCO Annual Meeting 2011. Journal of Clinical Oncology 2011;29(15 Suppl 1):8506.

SOURCES OF SUPPORT

Internal sources
• University of Padova, Padova, Italy.

External sources
• No sources of support supplied

DIFFERENCES BETWEEN PROTOCOL AND REVIEW

The final version of this review differs from the original protocol for a number of reasons:

• First of all, the critical revision of two authors (VCS (oncologist) and ML (dermatologist)) suggested a number of changes in
order to make the text clearer to non-melanoma experts. This required the rephrasing of many sentences throughout the text.
Moreover, a new author (VCS), who was not involved at the stage of writing the protocol, has joined the team of this work at the
review stage and has brought her viewpoint (she is an oncologist) on several aspects regarding this subject.
• Secondly, all authors have added new references and replaced others in order to provide readers with the best and most updated
information on this subject.

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 74

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
NOTES
A search in September 2015 found no relevant new results. Our Co-ordinating Editor confirmed that there is currently no new data
of relevance. Thus, this review has been marked stable because an update has not been considered necessary for two successive years.
Our Trials Search Co-ordinator will run a new search in September 2016 to re-assess whether an update is needed.

INDEX TERMS

Medical Subject Headings (MeSH)

Antineoplastic Agents [∗ therapeutic use]; Chemotherapy, Adjuvant [methods; mortality]; Disease-Free Survival; Interferon-alpha
[∗ therapeutic use]; Melanoma [∗ drug therapy; mortality; surgery]; Randomized Controlled Trials as Topic; Skin Neoplasms [∗ drug
therapy; mortality; surgery]

MeSH check words

Humans

Interferon alpha for the adjuvant treatment of cutaneous melanoma (Review) 75

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.