1. health and fitness
2. disease
3. cancer

Annals of Oncology 14: 358–365, 2003
DOI: 10.1093/annonc/mdg120
Review
Adjuvant therapy of cutaneous melanoma: the interferon debate
R. F. Kefford*
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Wentworthville, NSW; Sydney Melanoma Unit,
Sydney, NSW, Australia
Received 8 October 2002; revised 19 November 2002; accepted 3 Decmber 2002
Introduction
Few aspects of the modern treatment of cutaneous melanoma
(‘melanoma’) have provoked such controversy as the interpretation of clinical trials of interferon-α (IFN-α) in the adjuvant
treatment of high-risk disease following surgery. Partly, this has
been engendered by the high hopes attached to the early demonstration of the antitumour effects of IFN-α; partly, it derives from
the frustration and impotence experienced by oncologists in their
endeavours to find effective systemic treatments for this disease.
Additionally, it has been fuelled by the wide variability in the
results of successive randomised controlled trials of high-dose
IFN-α (HDI) the first of which demonstrated a significant benefit
over observation in overall survival (OS), a finding never subsequently repeated. Consequently, a trans-Atlantic divide has
ensued, with North American proponents declaring HDI ‘standard therapy’ for high-risk melanoma patients [1, 2], whereas
European oncologists, analysing the same data, state that the
routine use of IFN-α cannot be recommended outside the scope
of clinical trials [3]. The increasing maturity of the clinical trials
of IFN-α conducted in the 1980s and 1990s, together with recent
meta-analyses, provide an opportunity to revisit this question and
attempt to adjudicate in this ongoing clinical debate.
The challenge of adjuvant treatment of melanoma
Melanoma remains a major public health problem. The lifetime
incidence in New South Wales, Australia, is one in 25 for men
*Correspondence to: Professor R.F. Kefford, Department of Medicine,
Westmead Hospital, NSW 2145, Australia. Tel: +61-2-9845-6033;
Fax: +61-2-9867-2331; E-mail: [email protected]
© 2003 European Society for Medical Oncology
and one in 36 for women, making melanoma the fourth most
common cancer in men, and the third most common in women
[4].
Patients presenting with AJCC (American Joint Committee on
Cancer) stage I melanoma have an excellent prognosis (Table 1)
and are not generally considered for systemic adjuvant treatment.
However, a significant number of patients present each year with
disease categorised as high risk (<50% 10 year survival) and
intermediate risk (51–64% 10 year survival). By these criteria,
patients with stage IIA, IIB and IIIA disease could be regarded as
at intermediate risk, while those with IIC, IIIB and IIIC disease
are at high risk (Table 1). In the revised AJCC staging series, 29%
of the 17 600 patients fell into the intermediate-risk category,
and 7% into the high-risk group [5]. A recent audit of Sydney
Melanoma Unit data for 2002 reveals ∼8% of patients to be stage
III and 3% to be stage IIC at presentation (Helen Shaw, personal
communication).
Changes in staging and the impact of sentinel node
biopsy
All published adjuvant trials in melanoma have used the older
(1977) AJCC/UICC (Union Internationale Contre le Cancer)
staging system. Major changes have now been incorporated to
remove significant heterogeneity within certain staging groups,
and to incorporate the important additional prognostic information contributed by sentinel node biopsy (SNB) [5]. These
changes include reclassifying T groups by depth, inclusion of
ulceration to define Tb subgroups, reclassifying T4 tumours as
stage II (not stage III), the use of nodal number and the inclusion
of microscopic nodal classifications. The impact of this system is
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014
Despite the use of a variety of cytotoxic and immunotherapeutic agents in adjuvant trials in patients following
resection of high-risk early cutaneous melanoma, only interferon-α2b (IFN-α) has shown reproducible
efficacy. High-dose IFN-α (HDI) is superior to observation in prolonging relapse-free survival. There is still
no formal proof of a statistically significant advantage of HDI in prolonging overall survival. For this reason
the continued use of observation-only control arms is justified and desirable in adjuvant melanoma trials, and,
wherever possible, patients with resected high-risk and intermediate-risk melanoma should be entered on these
studies. The toxicity of HDI is high, but the majority of patients complete treatment with dose modification
and nearly all toxicity is rapidly reversible. There is now a useful body of information on the supportive care of
patients receiving HDI, and data on cost and quality-adjusted time without symptoms and toxicity (Q-TwiST)
to support its use in certain high-risk patients. Interim results from a trial of intermediate-dose IFN-α are
promising. These, and ongoing studies of pegylated IFN-α, and of shorter induction-only HDI promise refinements in treatment which may improve efficacy:toxicity ratios.
Key words: adjuvant therapy, interferon-α, melanoma
359
Table 1. Staging and prognosis of melanoma [5]
Stage
TNM
Thickness (mm)
Ulceration
No. of nodes
Nodal size
10 year survival
(rounded %)
IA
T1a
1
No
0
–
88
IB
T1b
1
Yes or level IV, V
0
–
79–83
T2a
1.01–2.0
No
0
–
IIA
T2b
1.01–2.0
Yes
0
–
T3a
2.01–4.0
No
0
–
IIB
T3b
2.01–4.0
Yes
0
–
T4a
>4.0
No
0
–
IIC
T4b
>4.0
Yes
0
–
32
57–63
IIIA
IIIB
Any
No
1
Micro
Any
No
2–3
Micro
N1a
Any
Yes
1
Micro
N2a
Any
Yes
2–3
Micro
N1b
Any
No
1
Macro
N2b
Any
No
2–3
Macro
N1b
Any
Yes
1
Macro
N2b
Any
Yes
2–3
Macro
N3
Any
Any
4
Micro/Macro
51–54
35–48
15–24
considerable stage migration. The importance of this is two-fold.
Firstly, the heterogeneity in prognosis contained within previously stratified subgroups in adjuvant trials may account for
some of the variation in outcomes between trials. Secondly, it is
critical that future trials utilise the full information available from
SNB in trial design.
USA) and IFN-α2b (Intron-A; Schering-Plough, Kenilworth,
NJ, USA) have molecular sequences that differ from one another
by a single amino acid at position 23 [10]. The majority of adjuvant trials in melanoma have been conducted using IFN-α2b.
Interferon biology
Following the demonstration of IFN-α activity against murine
B16 melanoma cell lines in vitro and in vivo [11], clinical trials of
the agent were conducted. Overall response rates for single agent
IFN-α in metastatic melanoma were ∼15%, with ∼5% complete
remissions [12]. There was no clear benefit for different doses in
the range 10 million Units (MU) three times per week to 50 MU
daily. Responses appeared to be more durable than those occurring for dacarbazine alone [13], but there was no additional
benefit in the advanced disease setting for combinations of dacarbazine plus IFN-α over single agent dacarbazine [14].
The interferons are a group of naturally occurring cellular
cytokines with important physiological functions in antiviral and
antitumour defence. They were first described in 1957 by Isaacs
and Lindenmann [6] and shortly afterwards were shown to display antitumour activity in experimental systems. The interferons
were initially classified according to their separation on HPLC
(high pressure liquid chromatograghy) profiles into α, β and
γ types. Later it became evident that IFN-α was produced principally by leukocytes, IFN-β by fibroblasts and IFN-γ by immune
cells. Induction of production follows exposure of the producer
cells to viruses, double-stranded RNA, polypeptides or cytokines
[7, 8]. The interferons bind to cell surface receptors which, after
oligomerisation, initiate a cascade of phosphorylation reactions
in JAK–Stat signalling intermediates, ultimately activating
transcription of IFN-stimulated genes (ISGs) [8, 9]. Expression
of ISGs has a variety of cellular effects. In the case of IFN-α,
relevant antitumour effects include direct cytotoxic and cytostatic effects on tumour cells, antiangiogenic effects, increased
expression of MHC (major histocompatibility complex), tumourspecific antigens and adhesion molecules. In addition, stimulatory effects are seen in T cells and natural killer cells [8, 9].
Recombinant IFN-α is produced by two pharmaceutical companies. IFN-α2a (Roferon A; Roche Laboratories, Nutley, NJ,
Activity of interferon against advanced melanoma
High-dose interferon-α2b as adjuvant
treatment for melanoma
Efficacy
The use of a HDI regimen for adjuvant treatment of melanoma
was pioneered by Kirkwood et al. [16]. The most commonly used
protocol employed an initial induction phase of 20 MU/m2 i.v.
daily for 5 days each week for 4 weeks, followed by a maintenance phase at 10 MU/m2 s.c. three times a week for 48 weeks
(total treatment duration of 52 weeks). The rationale for the initial
high-dose i.v. treatment phase was to provide maximal dose
intensity and minimise the induction of anti-IFN antibodies. The
five trials utilising HDI are summarised in Table 2.
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014
IIIC
N1a
N2a
64
360
Table 2. Clinical trials of high-dose IFN-α2b
Trial
IFN-α2b dose
Control
No. of
patients
Median FU
RFS
OS
Reference
NCCTG 83–7052
20 MU/m2 i.m. 3× a week
for 3 months
Observation
262
6.1 years
– (+ for LN+
subset only)
–
[15]
ECOG E1684
20 MU/m2 i.v. 5 days per week
for 4 weeks, 10 MU/m2 s.c.
3× a week for 48 weeks
Observation
287
6.9 years
+ at 6.9 years,
P = 0.0023
+ at 6.9 years,
P = 0.0237
[16]
12.6 years
+ at 12.6 years,
P = 0.01
– at 12.6 years,
P = 0.09
[17]
20 MU/m2 i.v. 5 days per week
for 4 weeks, 10 MU/m2 s.c.
3× a week for 48 weeks
Observation, LDI
(3 MU s.c.
3× a week)
642
6.2 years
+ (HDI),
P = 0.054
–
[18, 19]
Intergroup E1694
20 MU/m2 i.v. 5 days per week
for 4 weeks, 10 MU/m2 s.c.
3× a week for 48 weeks
GMK vaccine
774
1.9 years
+ P = 0.0025
+
[19, 20]
ECOG 2696
20 MU/m2 i.v. 5 days per week
for 4 weeks, 10 MU/m2 s.c.
3× a week for 48 weeks
GMK vaccine
107
2.0 years
+ P = 0.016;
P = 0.03
–
[19, 21]
ECOG, Eastern Cooperative Oncology Group; FU, follow-up; HDI, high-dose interferon-α; IFN, interferon; LDI, low-dose interferon-α; LN, lymph nodes;
MU, million Units; NCCTG, North Central Cancer Treatment Group; OS, overall survival; RFS, relapse-free survival.
ECOG 1684. The ECOG (Eastern Cooperative Oncology Group)
1684 trial enrolled 287 patients with (old) AJCC stage IIB or III
disease (T >4 mm, lymph nodes +/–; any T, pathological lymph
nodes +; regional lymph node recurrence). Patients all received
regional lymphadenectomy. Patients were randomised between:
(i) those receiving HDI (20 MU/m2 i.v. for 5 days each week for
4 weeks, followed by ‘maintenance’ therapy of 10 MU/m2 s.c.
three times weekly for a further 48 weeks); and (ii) observation.
At median follow-up of 6.9 years, both relapse-free survival
(RFS) and OS were significantly better for the HDI arm (RFS
1.72 versus 0.98 years, P = 0.0023; OS 3.82 versus 2.78 years,
P1 = 0.0237). Five-year estimated RFS was improved by 11%
[16]. Recently, a mature update of this study has been analysed at
a median follow-up of 12.6 years. In this analysis, the improvement in RFS (which is equivalent to metastasis-free survival, as
all patients sustained lymphadenectomy) persists, with 34 alive
relapse-free in the observation arm and 51 in the treated arm
(P = 0.01). The difference in OS disappeared, however (P1 = 0.09)
[17], an effect at least in part attributed to the fact that participants
in this trial are now entering their seventh decade, the median age
at entry having been 49 years [17]. An independent analysis of
E1684 also failed to show a statistically significant benefit in OS
[22], although the statistical methods in this analysis have been
challenged [23]. The gain in median survival for recipients of
HDI in the updated analysis was 13.8 months (45.8 months with
HDI compared with 32 months for observation).
On the basis of the data at 6.9 years the FDA (US Food and
Drug Administration) approved the use of IFN-α2b for (old
AJCC) stage IIB and III melanoma.
Intergroup E1690. In this three-arm trial, 642 similar patients
(608 eligible) were randomised following wide local excision
(but not mandatory lymph node dissection) between: (i) the same
HDI regime as ECOG 1684; (ii) 2 years of low-dose IFN-α2b
(LDI), 3 MU s.c. three times per week; and (iii) observation. At
52 months median follow-up, an advantage in 5-year estimated
disease-free survival was again seen for HDI (44% versus 35%,
P = 0.054) but not for LDI (40%). There was, however, no
advantage in OS for HDI (52%) or LDI (53%) over observation
(55%). At 74 months, there had been 108 deaths in the HDI arm
and 103 deaths in the observation arm of this study [19].
The failure of E1690 to replicate the advantages seen for HDI
in E1684 has been attributed to the marked improvement in
5-year OS in the observation arm, which was 55% for E1690
compared with just 37% for E1684 (P = 0.001) [18]. The investigators have explained this difference on the basis that 37 of
121 patients relapsing on the observation arm of E1690 received
salvage HDI, comprising all but one of the patients relapsing in
resectable regional lymph nodes. In this non-randomised setting,
in which considerable selection bias may have occurred, patients
receiving salvage therapy had a prolonged survival compared
with those who did not (2.2 years versus 0.8 years, P = 0.0024).
However, the improvement in survival of untreated (old AJCC)
stage II and III patients is a phenomenon observed internationally
between 1980 and 2000 (Figure 1). Factors involved may have
included better surgery and more accurate staging in later years,
or there may have been some unexplained changes in natural
history.
Further explanations for the lack of benefit of HDI in E1690
include the fact that patients with T4cN0 disease were eligible in
E1690, whereas all patients in E1684 had undergone lymphadenectomy.
Intergroup E1694. In this study, a comparison was made between
HDI (by then regarded by the trialists as ‘standard of care’) in one
arm and an experimental ganglioside vaccine, GMK, in resected
stage IIB/III patients. GMK consists of a well-defined melanoma
antigen, GM2, conjugated to keyhole limpet hemocyanin (KLH)
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014
Intergroup E1690
361
Figure 1. Historical changes in survival of (old AJCC) stage IIB/III
melanoma patients receiving no adjuvant therapy. The bars for E1684 and
E1690 show the survival of patients on the observation arms of those trials.
SMU, Sydney Melanoma Unit.
ECOG E2696. This small trial, designed to pilot combinations of
HDI and the vaccine GMK, compared two combinations of HDI
and the vaccine GMK (one concurrent and the other sequential)
against GMK vaccine alone in 107 high-risk melanoma patients
with resected stage IIB, III or IV disease, in a randomised phase II
design. Although relapse and death were not primary end points
of the study, Kaplan–Meier distributions of OS and RFS were
estimated at a median follow-up of 24 months, and demonstrated
a benefit in RFS for the two HDI-containing arms, compared with
the vaccine-only arm (P = 0.016; P = 0.03) [21]. There was no
benefit in OS.
Discussion of high-dose interferon/vaccine trials
The main question about the studies comparing HDI with vaccine
concerns the possibility that the vaccine had a deleterious effect
on survival.
The main arguments against a deleterious vaccine effect are the
following: (i) the antibody response to GMK had previously been
demonstrated to correlate with improved survival [24], and
patients on the vaccine arm of the E1694 trial who demonstrated
antibody responses at 1 month had a strong trend towards
improved survival compared to non-antibody responders; (ii) the
pooled data from vaccine arms had an improved survival compared with pooled data from observation arms in all HDI trials
[19] (however, as described above, such historical comparisons
are notoriously difficult in high-risk melanoma); (iii) the hazard
ratios for improved RFS on HDI were similar for E1694, E1690
and E1684; (iv) there was no evidence of any detrimental effect
of vaccination with GM2 plus BCG in a previous randomised
trial [24].
Notwithstanding these arguments, concern that the GMK vaccine may have been detrimental remains. An important precedent
for deleterious effects of vaccines in adjuvant cancer trials comes
from the meta-analysis by the Early Breast Cancer Trialists’
Collaborative Group (‘Oxford overview’) of adjuvant therapy
for early breast cancer in which 11 of 24 immunotherapy trials
showed a worse outcome for the immunotherapy arm compared
to observation [25]. There is at least a theoretical possibility that
antigenic vaccines could induce tolerance, or T-cell anergy,
particularly when tumour-associated antigens are presented in
the absence of costimulatory molecules. The end result could be a
negative therapeutic effect.
One important suggestion that the vaccine was indeed deleterious in this study is the fact that the Kaplan–Meier plot of survival
on GMK compares very closely with that of the observation arm
on the E1690 study, despite the fact that the HDI arm showed a
substantially better survival over that of identically staged and
treated patients on E1690 (Figure 2). It is difficult to explain this
similarity unless, in fact, there was a deleterious effect of vaccine
therapy on the survival of these patients.
Concerns have also been raised about a possible unequal distribution of patients with occult lymph node involvement amongst
the 141 T4N0M0 patients with no lymph node surgery who were
included in the study [26]. An over-inclusion of SNB-negative
patients in the HDI arm could significantly prejudice survival
benefits in that arm.
Pooled analyses of high-dose interferon trials
Pooled data for the 1915 patients entered on the four ECOG/
Intergroup adjuvant trials of HDI shown in Table 2 were reanalysed in 2001 with a median overall follow-up of 75 months
(33 months for those alive) [19]. These data revealed median RFS
of 1.4 years for observation, 3.0 years for HDI and 2.1 years for
GMK vaccine, with significance values of P = 0.05 (HDI versus
vaccine) and P = 0.01 (HDI versus observation) (log rank test).
Median OS was 4.1 years for observation, 6.2 years for HDI
and 3.8 years for vaccine, with P = 0.69 (HDI versus vaccine),
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014
and administered with the adjuvant QS-21 for 96 weeks. Of 880
patients entered, 774 were eligible for analysis. The trial was
closed after interim analysis indicated the inferiority of GMK
compared with HDI. At a median follow-up of 16 months, OS
in the HDI arm was 78% compared with 73% in the GMK arm
(P = 0.009). Two-year disease free survival was 62% and 49%,
respectively (P = 0.0015). HDI was associated with a treatment
benefit in all subsets of patients with zero to greater than or equal
to four positive nodes, but the greatest benefit was observed in the
node-negative subset (RFS hazard ratio = 2.07; OS hazard ratio =
2.71).
Figure 2. Changes in 2-year relapse-free survival in successive adjuvant
trials of high-dose interferon. Controls for E1684 and E1690 were
untreated; E1694 used a vaccine control.
362
Toxicity
Given general agreement about benefits in RFS there would
probably be little debate about the use of HDI as adjuvant treatment for high-risk early melanoma were it not for the high incidence of disabling toxicity, particularly during the i.v. induction
phase of the treatment protocol. This phase has been judged to be
an essential element in the treatment schedule because the separation of Kaplan–Meier curves of RFS occurs very early. The
major toxicities and reported incidence have been reviewed elsewhere [23] and are shown in Table 3. The most prominent acute
features are those of an influenza-like syndrome with constitutional features including fever, rigors, headache and myalgia. In
most studies, ECOG grade 3 and 4 toxicities are noted in approximately one-third of patients [23], but most toxicity is rapidly
reversible on cessation or dose reduction.
Dose reduction during HDI therapy was necessary in 33–58%
of patients during induction and 38–59% of patients during the
maintenance phase of the E1684, E1690 and E1694 adjuvant
trials [28], but the lower figure was achieved in the latest study,
suggesting increasing clinical skill in ameliorating toxicities.
With appropriate dose modification >80% of patients were able
to complete 12 months of therapy on the E1694 trial [23]. Nonetheless, in the E1684 and E1690 trials, toxicity classified as
‘severe’ was experienced by 67.1% and 52.6% of patients,
respectively, for a mean of 7.3 months [29].
Considerable skill has been accumulated in the nursing care of
patients on HDI, and in the symptomatic relief of acute toxicity.
This includes the administration of HDI late in the day, the liberal
use of paracetamol and non-steroidal anti-inflammatory medication to relieve fever and myalgia [30], and the use of prochlorperazine, metoclopramide and ondansetron or granesitron for
nausea and emesis. Fluid support is important to prevent dehydration [23]. The routine prophylactic use of antidepressants like
paroxetine has been shown to prevent serious depressive reactions [31–33], and mood stabilisers such as gabapentin have also
been advocated [34]. Fatigue can be alleviated in certain cases
using supportive elements such as light exercise, nutritional care,
encouragement of non-caffeine containing fluids and, in some
Table 3. Toxicity of high-dose interferon-α
Toxicity
Frequency
Acute toxicity
Fever
Common
Rigors
Common
Headache
Common
Nausea
Common
Emesis
Occasional
Anorexia
Common
Myalgia
Common
Supraventricular tachyarrhythmias
Rare
Neutropenia
Common
Hepatic enzyme elevation
Common
Hyperbilirubinaemia
Occasional
Rhabdomyolysis
Rare
Chronic Toxicity
Fatigue
Common
a
Depression
Common
Cognitive dysfunction
Common
Coma
Rare
Psychosis
Rare
Weight loss
Common
Anorexia
Common
Proteinuria
Occasional
Interstitial nephritis
Rare
Hyper-triglyceridemia
Occasional
Pancreatitis
Rare
Thyroid dysfunction
Occasional
Peripheral neuropathy
Rare
Retinal microvascular changes
Rare
Alopecia
Occasional
b
Skin rashes
Common
a
Patients with a history of psychiatric illness should be managed
in collaboration with an experienced psychiatrist [23].
b
High-dose interferon-α treatment may be contraindicated in the
presence of severe psoriasis [23].
cases, the use of megestrol acetate and, in severe cases, methylphenidate. The latter is the subject of a current randomised
controlled clinical trial by ECOG. Corticosteroids, which would
potentially relieve many of the side-effects of HDI, are contraindicated because of potential interference with the immune
mechanisms of IFN-α action, and demonstrated abrogation of
antitumour effects of IFN-α in animal models.
HDI induces inhibition of up to 60% of the cytochrome P450
enzyme isoforms in the liver, and the degree of inhibition correlates with gastrointestinal, neurological, haematological and
influenza-like toxicities [28]. These enzymes are responsible for
the metabolism of many agents used in the treatment of these
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014
P = 0.01 (HDI versus observation). The main problems with this
particular pooled analysis are the heterogeneity between the trials
being compared in terms of stage of disease and trial design, and
the lack of maturity of the E1694 and E2696 trials which heavily
influence the positive outcome.
A more formal meta-analysis of HDI trials was also performed,
using only published trials with an observation control arm, and
therefore excluding E1694. This analysis showed no significant
effect of HDI on OS (12% reduction in mortality odds ratio,
standard deviation 8, 2P = 0.1), but a significant effect on RFS
(24% reduction in odds ratio of recurrence, standard deviation 7,
2P = 0.0009) [27].
A review of a number of selected HDI trials, including three of
those summarised in Table 2, showed no evidence of benefit in
OS [22]. However, there was such heterogeneity between the
trials that a formal meta-analysis was not possible, and the large
E1694 trial was not included.
363
patients, including most antidepressants, codeine, benzodiazepines
and warfarin. Substantial dose modification may be necessitated
by these potential drug interactions.
Acute hepatic transaminitis is common, and normally reversible on dose reduction or cessation. Rarely, fatal hepatic necrosis
has followed the administration of IFN-α in spite of abnormal
liver function tests [16]. However, there have been no toxic
deaths on cooperative group studies of HDI since the introduction
of formal dose modification guidelines [23].
With maintenance therapy, more chronic toxicities become
apparent, including anorexia, malaise and weight loss. These
later toxicities are complex results of dysgeusia, low-grade fever
and nutritional compromise. Thyroid dysfunction and possible
autoimmune processes may also contribute [12].
HDI: what should oncologists advise their high-risk
patients?
Ideally, patients with high-risk primary melanoma should be
entered on clinical trials that are attempting to answer critical
questions regarding longevity, quality of life and treatment costs.
As no agent has been demonstrated definitively to prolong OS for
any group with high-risk disease it is desirable and ethical to
include an observation arm in the design of these trials, even for
node-positive groups.
For patients outside of clinical trials observation, not HDI
remains the standard of care, as OS remains the key end point for
adjuvant therapy. However, patients without significant comorbidity or contraindications to HDI deserve a full explanation of the
controversy regarding its use, including the fact that all analysts
are agreed that it is the only agent showing activity against
melanoma in the adjuvant setting and that it prolongs 5-year RFS
by ∼10% at the expense of considerable, but rapidly reversible,
toxicity. The meta-analysis of HDI trials showed a 24% reduction
in the odds of recurrence for IFN-α treated patients (2P = 0.0009)
[27]. A decision rule derived from that proposed by Kilbridge et al.
[29] may assist clinicians in helping patients make a decision
regarding HDI: treat a patient with HDI if he or she agrees with
the statement, “If I had a serious disease, I would gladly accept
feeling lousy for a year if it improved my chances of having a
longer period without the disease”, and if he or she answers ≤10%
to the following statement, “I would put up with the side-effects
of HDI treatment only if it decreased the chance of the melanoma
returning in 5 years time by at least x%”. Many such patients
choose an ‘attempt’ at HDI on the clear understanding that they
are free to abandon it at any point if toxicity is prohibitive.
It is imperative that HDI be administered strictly according to
guidelines, and that dose reductions are only carried out as specified for the more recent ECOG/Intergroup trials, and summarised
recently by Kirkwood [23]. There may be a temptation for
clinicians treating patients off study towards leniency in dose
modification for the common toxicities of fatigue and influenzalike syndrome. More generous dose reductions than those used
in published trials could result in a substantial reduction in any
beneficial effect on RFS.
Cost-effectiveness
Low and intermediate dose interferon-α2b
The cost-effectiveness of HDI was evaluated, based solely on the
significantly positive E1684 trial [37]. In this trial, the cost of
HDI per life-year gained ranged from US$13700 after a projected 35 years to US$32600 at 7 years (the median follow-up of
E1684). The benefits of IFN-α2b projected over a lifetime
The use of low- and medium-dose IFN-α2b as adjuvant treatment
of melanoma has been reviewed elsewhere [1–3]. Some trials
have demonstrated a delay in recurrence for IFN treated arms in
these trials, and a meta-analysis showed a 13% reduction in the
odds of recurrence for patients treated with low-dose IFN-α, but
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014
Time without symptoms and toxicity. An analysis of qualityadjusted time without symptoms and toxicity (Q-TwiST) was
performed for the E1684 trial of HDI versus observation [35].
The HDI group had more quality-of-life-adjusted time than the
observation group regardless of the relative valuations placed on
time with toxicity and time with relapse. There was a mean gain
of 8.9 months without relapse (P = 0.03) and 7 months of OS time
(P = 0.02) for the HDI patients after 84 months of follow-up as
compared with the observation group. This gain was significant
(P <0.05) for patients who consider time with toxicity to have a
high relative value and time with relapse to have a low relative
value. In contrast, for patients who valued time with toxicity as
being similar to time with relapse, the quality-adjusted gain for
HDI was not statistically significant. An analysis stratified
according to tumour burden indicated that the benefit of HDI was
greatest in node-positive patients. These data are heavily influenced by the highly significant differences in RFS and OS seen in
the seminal E1684 study.
In a further attempt to quantify the trade-offs between HDI
toxicity and survival, Kilbridge et al. assessed patient utilities for
health states associated with IFN-α2b therapy in 107 low-risk
melanoma patients who were not receiving adjuvant treatment
[36]. At least half the patients were willing to tolerate mild/
moderate and severe toxicity from HDI for 4% and 10%
improvements, respectively, in 5-year disease-free survival. It
should be noted that only the E1684 trial demonstrated an
improvement with HDI in 5-year RFS of >10% (26% versus
37%). However, in a further study of quality-of-life-adjusted
survival (QAS) in E1684, IFN-α resulted in an increase in QAS
for all sets of patient utilities, however this only reached significance for 16% of patients; using E1690 data, 77% of patients
experienced a benefit in QAS from IFN-α and 23% experienced
a decrease in QAS, and neither of these effects was statistically
significant [29].
yielded incremental cost per life-year or quality-adjusted lifeyear that were <US$16 000. This compares favourably with other
accepted adjuvant therapies of breast and colorectal cancer. It
must be re-emphasised, however, that E1684 is the only trial that
has shown an OS benefit of HDI versus observation, and there
has been no re-analysis of cost-effectiveness against recent
updated follow-up of this trial at 12.6 years in which the OS
benefit has disappeared [17].
364
no difference in OS [27]. It is likely, however, that this benefit is
confined to stage IIB patients, and important prognostic factors
such as sentinel node status and primary tumour ulceration were
not routinely evaluated.
The EORTC (European Organisation for Research and
Treatment of Cancer) have recently performed a preliminary
analysis on their 18952 trial which compares IFN-α2b at 10 MU
s.c. three times per week for 1 year with 5 MU s.c. three times per
week for 2 years and with an observation alone arm. These doses
are approximately half the total accumulated IFN-α2b dose on
the HDI trials. This preliminary analysis showed an improvement
for distant metastasis-free survival for the 2-year IFN arm
(P = 0.0145), with acceptable toxicity (10% grade 3 or 4) [38].
Distant metastasis-free survival is a potential surrogate for OS, as
it overcomes the confounding effect of locoregional recurrence,
for which there is a salvage rate of ∼30%.
Existing refinements in staging, including the use of sentinel
node biopsy and the use of tumour ulceration as a prognostic
factor, will improve the stratification of patients on adjuvant
studies. Further improvements will occur with the advent of gene
expression profiling [39].
As several lower dose IFN-α trials show a ‘banana-shaped’
difference between treated and observation RFS curves, a legitimate question concerns the duration of treatment. Several current
trials are addressing this question, including the EORTC 18991
trial of slow release pegylated (PEG)-IFN-α2b once a week for
5 years versus observation in patients with resected stage III
melanoma.
In an attempt to shorten treatment duration with a more intensive regime, the USA S0008 trial compares 9 weeks of a modified
biochemotherapy regime (cisplatin, vinblastine, dacarbazine,
IFN-α2b and IL-2) [40] with 1 year of standard HDI.
The E1697 Intergroup trial compares the induction phase alone
(1 month of HDI) versus observation in intermediate risk (stage II
T3) patients. This is a particularly important study as it is possibly
the only remaining trial of HDI with an observation control arm.
The early separation of survival curves in the E1684 and E1690
trials, and the failure of HDI trials without the induction
component (such as NCCTG 93-7052) further emphasises the
importance of this investigation.
The Sunbelt Melanoma Trial investigates the use of standard
HDI versus observation in patients with isolated regional lymph
node metastases after lymphadenectomy, and observation versus
lymphadenectomy alone versus lymphadenectomy plus 1-month
of induction HDI in patients with polymerase chain reaction
(PCR)-positive isolated regional sentinel lymph nodes.
Conclusions
Until agents of improved efficacy and reduced toxicity are
available, all patients with intermediate- and high-risk resected
melanoma should be entered on randomised clinical trials wherever possible. The use of observation control arms in these
References
1. Gray RJ, Pockaj BA, Kirkwood JM. An update on adjuvant interferon for
melanoma. Cancer Control 2002; 9: 16–21.
2. Sondak VK, Sabel MS. Adjuvant therapy of melanoma: does any of it
really work? American Society of Clinical Oncology Educational Book.
Baltimore, MD: Lippincott Williams and Wilkins 2002; 190–196.
3. Punt CJ, Eggermont AM. Adjuvant interferon-α for melanoma revisited:
news from old and new studies. Ann Oncol 2001; 12: 1663–1666.
4. Tracey EA, Supramaniam R. Cancer in New South Wales: incidence and
mortality 2000 featuring projections to 2010 for selected sites. Sydney,
Australia: The Cancer Council NSW 2002.
5. Balch CM, Buzaid AC, Soong SJ et al. Final version of the American
Joint Committee on cancer staging system for cutaneous melanoma.
J Clin Oncol 2001; 19: 3635–3648.
6. Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc Roy
Soc (London) 1957; 147: 258–267.
7. Pfeffer LM, Dinarello CA, Herberman RB et al. Biological properties of
recombinant α-interferons: 40th anniversary of the discovery of interferons. Cancer Res 1998; 58: 2489–2499.
8. Williams BRG. Interferon-α and -β: basic principles and preclinical
studies. In Rosenberg SA (ed): Principles and Practice of the Biologic
Therapy of Cancer, 3rd edition. Philadelphia, PA: Lippincott Williams
and Wilkins 2000.
9. Jonasch E, Haluska FG. Interferon in oncological practice: review of
interferon biology, clinical applications, and toxicities. Oncologist 2001;
6: 34–55.
10. Weiss K. Safety profile of interferon-α therapy. Semin Oncol 1998; 25
(Suppl 1): 9–13.
11. Bart RS, Porzio NR, Kopf AW et al. Inhibition of growth of B16 murine
malignant melanoma by exogenous interferon. Cancer Res 1980; 40:
614–619.
12. Kirkwood JM. Interferon-α and -β: clinical applications: melanoma. In
Rosenberg SA (ed): Principles and Practice of the Biological Therapy of
Cancer, 3rd edition. Philadelphia, PA: Lippincott Williams and Wilkins
2000.
13. Agarwala SS, Kirkwood JM. Interferons in melanoma. Curr Opin Oncol
1996; 8: 167–174.
14. Thomson DB, Adena M, McLeod GR et al. Interferon-α 2a does not
improve response or survival when combined with dacarbazine in metastatic malignant melanoma: results of a multi-institutional Australian
randomized trial. Melanoma Res 1993; 3: 133–138.
15. Creagan ET, Dalton RJ, Ahmann DL et al. Randomized, surgical
adjuvant clinical trial of recombinant interferon α-2a in selected patients
with malignant melanoma. J Clin Oncol 1995; 13: 2776–2783.
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014
Future directions
studies continues to be justifiable and ethical, but patients with
high-risk disease deserve a full explanation of HDI treatment,
including the current controversy regarding the interpretation of
OS data. They should be told that there is widespread agreement
that it prolongs relapse-free 5-year survival by ∼10% at the
expense of 12 months of treatment involving considerable toxicity, and that the impact on RFS can only reasonably be expected
when this drug is administered according to strict guidelines by
experienced physicians.
The further refinement of risk groups based on the use of
molecular genetic factors, particularly gene expression profiles,
promises significant improvement in the sophistication of trial
design and outcome.
365
29. Kilbridge KL, Cole BF, Kirkwood JM et al. Quality-of-life-adjusted
survival analysis of high-dose adjuvant interferon α-2b for high-risk
melanoma patients using intergroup clinical trial data. J Clin Oncol 2002;
20: 1311–1318.
30. Miller RL, Steis RG, Clark JW et al. Randomized trial of recombinant
α 2b-interferon with or without indomethacin in patients with metastatic
malignant melanoma. Cancer Res 1989; 49: 1871–1876.
31. Musselman DL, Lawson DH, Gumnick JF et al. Paroxetine for the
prevention of depression induced by high-dose interferon α. N Engl
J Med 2001; 344: 961–966.
32. Capuron L, Gumnick JF, Musselman DL et al. Neurobehavioral effects
of interferon-α in cancer patients: phenomenology and paroxetine
responsiveness of symptom dimensions. Neuropsychopharmacology
2002; 26: 643–652.
33. Hauser P, Soler R, Reed S et al. Prophylactic treatment of depression
induced by interferon-α. Psychosomatics 2000; 41: 439–441.
34. Greenberg DB, Jonasch E, Gadd MA et al. Adjuvant therapy of
melanoma with interferon-α-2b is associated with mania and bipolar
syndromes. Cancer 2000; 89: 356–362.
35. Cole BF, Gelber RD, Kirkwood JM et al. Quality-of-life-adjusted
survival analysis of interferon α-2b adjuvant treatment of high-risk
resected cutaneous melanoma: an Eastern Cooperative Oncology Group
study. J Clin Oncol 1996; 14: 2666–2673.
36. Kilbridge KL, Weeks JC, Sober AJ et al. Patient preferences for adjuvant
interferon α-2b treatment. J Clin Oncol 2001; 19: 812–823.
37. Hillner BE, Kirkwood JM, Atkins MB et al. Economic analysis of
adjuvant interferon α-2b in high-risk melanoma based on projections
from Eastern Cooperative Oncology Group 1684. J Clin Oncol 1997; 15:
2351–2358.
38. Eggermont AM, Kleeberg UR, Ruiter DJ, Suciu S. The European Organization for Research and Treatment of Cancer Melanoma Group Trial
experience with more than 2000 patients evaluating adjuvant treatment
with low or intermediate doses of interferon-α-2b. Amercian Society of
Clinical Oncology Education Book. Alexandria, VA: Lippincott
Williams and Wilkins 2001; 88–93.
39. Bittner M, Meltzer P, Chen Y et al. Molecular classification of cutaneous
malignant melanoma by gene expression profiling. Nature 2000; 406:
536–540.
40. Buzaid AC, Atkins M. Practical guidelines for the management of
biochemotherapy-related toxicity in melanoma. Clin Cancer Res 2001;
7: 2611–2619.
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014
16. Kirkwood JM, Strawderman MH, Ernstoff MS et al. Interferon α-2b
adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern
Cooperative Oncology Group trial EST 1684. J Clin Oncol 1996; 14:
7–17.
17. Kirkwood JM, Ibrahim J, Manola J. High-dose interferon versus GM2
vaccine in high-risk malignant melanoma. J Clin Oncol 2001; 19: 4350.
18. Kirkwood JM, Ibrahim JG, Sondak VK et al. High- and low-dose
interferon α-2b in high-risk melanoma: first analysis of Intergroup trial
E1690/S9111/C9190. J Clin Oncol 2000; 18: 2444–2458.
19. Kirkwood JM, Manola J, Ibrahim J et al. Pooled-analysis of four ECOG/
Intergroup trials of high-dose interferon α-2b (HDI) in 1916 patients
with high-risk resected cutaneous melanoma. Proc Am Soc Clin Oncol
2001; 20: 350a (Abstr 1395).
20. Kirkwood JM, Ibrahim JG, Sosman JA et al. High-dose interferon α-2b
significantly prolongs relapse-free and overall survival compared with
the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III
melanoma: results of intergroup trial E1694/S9512/C509801. J Clin
Oncol 2001; 19: 2370–2380.
21. Kirkwood JM, Ibrahim J, Lawson DH et al. High-dose interferon α-2b
does not diminish antibody response to GM2 vaccination in patients with
resected melanoma: results of the Multicenter Eastern Cooperative
Oncology Group phase II trial E2696. J Clin Oncol 2001; 19: 1430–1436.
22. Lens MB, Dawes M. Interferon α therapy for malignant melanoma: a
systematic review of randomized controlled trials. J Clin Oncol 2002; 20:
1818–1825.
23. Kirkwood JM, Bender C, Agarwala S et al. Mechanisms and management of toxicities associated with high-dose interferon α-2b therapy.
J Clin Oncol 2002; 20: 3703–3718.
24. Livingston PO, Wong GY, Adluri S et al. Improved survival in stage III
melanoma patients with GM2 antibodies: a randomized trial of adjuvant
vaccination with GM2 ganglioside. J Clin Oncol 1994; 12: 1036–1044.
25. Group EBCTC. Systemic treatment of early breast cancer by hormonal,
cytotoxic or immune therapy. Lancet 1992; 339: 71–85.
26. Kretschmer L, Neumann C. Sentinel-node technique will change the
design of clinical trials in malignant melanoma. J Clin Oncol 2002; 20:
2208.
27. Wheatley K, Hancock B, Gore M et al. Interferon-α as adjuvant therapy
for melanoma: a meta-analysis of the randomised trials. Proc Am Soc
Clin Oncol 2001; 20: (Abstr 1394).
28. Kirkwood JM. Adjuvant therapy of melanoma. San Francisco: ASCO
Virtual Meeting 2001.
Downloaded from http://annonc.oxfordjournals.org/ by guest on September 9, 2014