ARTICLE
Auteur(s) : Carmen Loquai1, Dorothee
Nashan2, Peter Hensen3, Thomas A
Luger3, Stephan Grabbe1, Cord
Sunderkötter3, Meinhard Schiller3
1Department of Dermatology, University of Mainz,
Mainz, Germany
2Department of Dermatology, University of Freiburg,
Freiburg, Germany
3Department of Dermatology, University of Münster,
Von-Esmarch-Str. 58, 48149 Münster, Germany
accepté le 27 Août 2007
Among the numerous therapeutic modalities investigated so far,
recombinant IFN-α is the only single drug that has a reproducible
and significant adjuvant effect in adjuvant therapy of high-risk
melanoma. In 1996, Kirkwood et al. demonstrated that high-dose
IFN-α-2b significantly prolongs not only disease-free survival
(DFS), but also limited overall survival rates in patients with
lymph node metastasis or with melanomas thicker than 4.0 mm
[1, 2]. Since then, several meta-analyses of pooled results of 3
randomized trials conducted by the Eastern Cooperative Oncology
Group clearly confirmed reductions in the recurrence of high-risk
melanoma, though they failed to prove a reproducible and
significant survival benefit [3, 4]. Adjuvant therapy with low-dose
IFN-α for resected primary melanoma thicker than 1.5 mm
without clinically detectable lymph node metastases, demonstrated a
significant benefit in terms of disease-free survival, though they
did not reveal a significant increase in overall survival [5, 6].
Therapy with IFN-α is associated with considerable side effects,
such as a flu-like syndrome, fatigue, myelosuppression and
hepatotoxicity. Other clinically relevant side effects – such as
depression, anxiety, agitation and anorexia – occur less
frequently, but are still of major relevance as they lead to
substantial dose reduction and even discontinuation of therapy
[5-10].
Fluck and colleagues have shown in their retrospective analysis
on patients treated with high dose IFN-α in their single
institution, that the absolute dosage of IFN-α tolerated by
patients was a transient, independent predictor of relapse-free and
overall survival [11]. Although this result needs further
evaluation by prospective randomized studies it further justifies
efforts to optimize dosage schemes and duration of therapy with
IFN-α in order to further improve disease free survival or to
attain a significant increase in overall survival. With standard
IFN-α-2a, a highly variable drug concentration is present
throughout the dosing interval due to the high systemic clearance
and a serum half-life of less than 3 hours [12]. One might
speculate that these pharmacokinetic properties are responsible for
reduced efficacy and increased side effects. By contrast, a new
pegylated formulation of IFN-α, i.e. PEG-IFN-α-2a, presents a more
sustained high blood level due to its prolonged absorption
half-life (50 h), restricted volume of distribution (8-12 l),
and decreased clearance (94 ml h–1) [13, 14]. These
qualities were associated with a significantly higher efficacy of
PEG-IFN-α-2a in combination with ribavirin in the treatment of
chronic hepatitis C when compared to standard IFN-α/ribavirin
therapy [15, 16]. These significantly superior, sustained,
virological response rates have made the combination of ribavirin
with both of the commercially available PEG-IFN-α formulations the
current standard of care in hepatitis C [15-17]. In these studies
the tolerability of standard IFN-α and PEG-IFN-α were similar
[12].
In melanoma, the adjuvant antitumoural rather than the antiviral
effects of IFN-α come into play. In light of the importance that
cumulative or sustained IFN-α dosages have on the antitumour
efficacy, dose limiting side effects may become a major factor for
the clinical outcome. In this context the advantages of the
pharmacokinetics of PEG-IFN-α have not been explored yet for
melanoma patients. One should assume, however, that a reduction of
side effects allows a more constant administration of the intended
target dose and thus secures the antineoplastic efficacy for a high
number of patients. As such, there has been initial evidence that
pegylated IFN-α was very well tolerated in therapy of renal cell
cancer [18, 19] and neuroendocrine gastroenteropancreatic
carcinomas [20], with no decrease in efficacy.
Therefore, the aim of this retrospective study was to evaluate
if PEG-IFN-α-2a would have a more favourable safety profile with
less side effects in adjuvant treatment of high-risk melanoma
patients than is usually experienced with high doses of standard
IFN-α or also with low doses of standard IFN.
Materials and methods
Patients
A review of medical records was performed on all patients with
histologically proven intermediate and high-risk melanoma who were
presented to the University of Münster, Department of Dermatology,
between December 2002 and December 2004 and who commenced adjuvant
PEG-IFN-α-2a treatment (180 μg/week (wk) subcutaneously (s.c.))
after inter-individual decision. Two abstractors (CL and MS)
independently evaluated each case, and then reconciled findings.
The following patients’ characteristics were recorded: age, sex,
Breslow thickness, Clark’s Level, ulceration of the primary tumour,
sentinel lymph node (SLN) biopsy status, primary tumour site, stage
of melanoma (according to the American Joint Committee on Cancer
(AJCC 2002)), side effects, dose modifications and discontinuation
of therapy. Side effects experienced by patients on PEG-IFN-α-2a
were graded according to the National Cancer Institute common
toxicity criteria (CTC-criteria). Only cases that delivered these
requested parameters were included for subsequent analysis.
Treatment schedule
The majority of trials with PEG-IFN-α-2a against hepatitis C [21,
22], renal cell cancer [18, 19] or chronic myelogenous leukemia
revealed an effective dosing at 180 μg/wk while a dose-limiting
toxicity was 540 μg/wk. Based on these findings, individuals
electing to be treated with adjuvant IFN-α received a PEG-IFN-α-2a
regimen (180 μg once a week for 1 year, Pegasys, recombinant
PEG-IFN-α-2a; Hoffmann-La Roche, Basel, Switzerland). Patients were
trained to self-administer the drug subcutaneously at home. Higher
toxicity was managed by a dose reduction of approximately 25% (down
to 135 μg/wk); treatment was discontinued if a severe or
life-threatening effect occurred, in the event of progression of
the melanoma to metastatic disease, or if the patient chose to halt
the treatment.
Statistical analyses
In order to compare adverse events between patients receiving
standard and PEG-IFN-α published data from the AIM-HIGH study
(adjuvant low-dose IFN-α in high-risk melanoma for 2 years) and
data from high-dose-IFN-α ECOG melanoma trials were used [8, 23].
The equality of proportion of patients experiencing adverse events
while undergoing adjuvant treatment for resected melanoma was
assesed using Fishers’s exact test. Two-tailed P-values ≤ 0.05 were
considered statistically significant.
Results
Definition of study population
The study cohort consisted of 18 high-risk cutaneous melanoma
patients in which adjuvant immunotherapy with PEG-IFN-α-2a was
initiated between December 2002 and December 2004. Patient
characteristics are shown in table 1.
Six patients had Stage II and 12 had Stage III disease according to
AJCC 2002. Approximately two-thirds of the patients had primary,
resected melanoma, while one-third had recurrent disease (i.e.
lymph node, satellite or in transit metastases) at study entry
(table 1). Of these, 3 patients had
already undergone adjuvant systemic chemotherapy in combination
with low-dose IFN-α or with low-dose IFN-α alone. In addition, 3
patients had a history of regional radiotherapy as an adjuvant
treatment strategy. No patient had evidence of distant metastases,
based on physical examination, laboratory tests or imaging
evaluations performed before the initiation of adjuvant
PEG-IFN-α-2a treatment.
Table 1 Patient characteristics
|
No.
|
%
|
|
No. of patients, total
|
18
|
100
|
|
Sex
|
|
|
|
Male
|
8
|
44
|
|
Female
|
10
|
56
|
|
Age
|
|
|
|
Median
|
59 years
|
|
|
Min
|
23 years
|
|
|
Max
|
73 years
|
|
|
Primary tumor site
|
|
|
|
Head/neck
|
4
|
22
|
|
Trunk
|
3
|
17
|
|
Extremities
|
9
|
50
|
|
Anogenital
|
1
|
6
|
|
No known primary
|
1
|
6
|
|
Melanoma subtype
|
|
|
|
SSM
|
3
|
17
|
|
NM
|
7
|
39
|
|
ALM
|
0
|
0
|
|
LM
|
0
|
0
|
|
Mucosal Melanoma
|
0
|
0
|
|
Othera
|
7
|
39
|
|
Not applicableb
|
1
|
6
|
|
Clark level
|
|
|
|
I
|
0
|
0
|
|
II
|
0
|
0
|
|
III
|
0
|
0
|
|
IV
|
11
|
61
|
|
V
|
2
|
11
|
|
Unknown
|
4
|
22
|
|
Not applicableb
|
1
|
6
|
|
Breslow depth
|
|
|
|
T1 (≤ 1.0)
|
0
|
0
|
|
T2 (1.01-2.0)
|
3
|
17
|
|
T3 (2.01-4.0)
|
9
|
50
|
|
T4 (> 4.01)
|
3
|
17
|
|
Unknown
|
2
|
11
|
|
Not applicableb
|
1
|
6
|
|
Ulceration
|
|
|
|
Yes
|
2
|
11
|
|
No
|
11
|
61
|
|
Unkown
|
4
|
22
|
|
Not applicableb
|
1
|
6
|
|
No. of nodes involved
|
|
|
|
No
|
0
|
0
|
|
1
|
6
|
33
|
|
2 to 3
|
0
|
0
|
|
≥ 4
|
0
|
0
|
|
Not applicable
|
12
|
67
|
|
Lymph node metastasis
|
|
|
|
Micrometastasis
|
5
|
28
|
|
Macrometastasis
|
1
|
6
|
|
Intransit met(s)/satellite(s) without metastatic nodes (pN2c)
|
2
|
11
|
|
Not applicable
|
10
|
56
|
|
Disease status
|
|
|
|
Primary disease
|
12
|
67
|
|
Recurrent disease
|
6
|
33
|
|
Primary unknown
|
0
|
0
|
|
AJCC Stadien
|
|
|
|
IIA
|
3
|
17
|
|
IIB
|
3
|
17
|
|
IIC
|
0
|
0
|
|
IIIA
|
4
|
22
|
|
IIIB
|
7
|
39
|
|
IIIC
|
1
|
6
|
|
IV
|
0
|
0
|
|
Adjuvant pretreatment
|
|
|
|
No
|
13
|
72
|
|
Low-dose IFN-α
|
1
|
6
|
|
Low-dose IFN-α + Chemo
|
2
|
11
|
|
Chemotherapy only
|
0
|
0
|
|
Local/regional radiation
|
2
|
11
|
aOne case of amelanotic melanoma, one case of malignant
blue nevus and 5 cases undocumented by reporting pathology.
bNo known primary.
Side effects
Side effects were reported by all patients at some point during the
treatment period. Their quality was similar as reported for
conventional IFN-α, but no additional or new side effects occurred.
A summary of toxicities is presented in table
2. Flu-like symptoms including fatigue, myalgia or headache
were reported by the majority of the patients: Fatigue occurred in
61% (Grade I/II), myalgia in 44% (Grade I/II) and headache in 33%
of the patients. One patient with headache experienced Grade III
toxicity. Two patients (11%) had a mild increase of CK,
additionally associated with myalgia in 1 patient.
Mild gastrointestinal symptoms (Grade I) were reported in 33% (n
= 6) of patients. Two patients (11%) experienced weight loss (Grade
I/II), which in 1 patient was associated with tumour progression.
Fourteen patients (78%) experienced a mild to moderate degree of
neutropenia (Grade I/II). Two cases of erysipelas requiring
intravenous antibiotics and hospitalization were rather due to
lymphedema subsequent to lymph node dissection (LAD) than to
PEG-IFN. Both patients had undergone LAD prior to start of
treatment. Anemia (56%) and thrombocytopenia (72%) occurred with a
lower frequency and were not severe (Grade I/II) except for 1
patient, who developed Grade III thrombocytopenia. In this case a
dose reduction by 25% was performed. Hepatotoxicity, i.e. increases
in AST/ALT, GGT and alkaline phosphatase, occurred in 72%, 72%, and
17% of the patients, respectively. Only 3 patients experienced
Grade III hepatotoxicity.
Depression and anxiety as psychiatric side effects occurred in
33% and 6% of patients, respectively. Two of them required
anti-depressant medication for Grade III symptoms and they
discontinued the treatment course (tables 1 and
4).
Further side effects which occurred in mild to moderate degrees
(Grade I/II) were: dizziness (33%), arthralgia (22%), increased
sweating (28%), hair loss (17%), chills (11%), rash (11%), local
skin reaction (11%), erectile dysfunction (11%), dyspnea (6%) and
blurred vision (6%) (table 2).
Mild (Grade I) sicca-symptoms occurred in 7 patients (39%): in 1
patient it was associated with dysgeusia. Taste alteration (Grade
I/II) was reported by 2 patients during treatment. Four patients
developed thyroid dysfunction with clinically apparent
hyperthyroidism accompanied by the induction of thyroidal
antibodies (anti-thyreoglobulin-antibodies (anti-TG-AB (n = 4)),
anti-TSH-receptor-AB (n = 4), anti-thyroidperoxidase (TPO)-AB (n =
3)). During the course of therapy, 3 of them were complicated by
clinically apparent hypothyroidism, requiring thyroid hormone
supplementation. One patient turned positive for anti-TG-AB and
anti-TPO-AB without any thyroid dysfunction.
Three patients were positive for ANAs before therapy. Five
patients became ANA-positive under PEG-IFN-α2a therapy. However,
only 1 of them developed an autoimmune thyroiditis as mentioned
above. Another patient showed an erythematous rash with slight
scaling located on the face and décolleté. No further clinical
symptoms occurred and the exanthema faded after cessation of
therapy.
Table 2 Adverse events in patients treated with
Peg-IFN-α-2a
|
Adverse eventa
|
No.
|
%
|
|
Any grade
|
Grade III-IV
|
Any grade
|
Grade III-IV
|
|
Constitutional side-effects/fatigue
|
14
|
0
|
78
|
0
|
|
Fatigue
|
11
|
0
|
61
|
0
|
|
Myalgia
|
8
|
0
|
44
|
0
|
|
Headache
|
6
|
1
|
33
|
6
|
|
Gastrointestinal
|
6
|
0
|
33
|
0
|
|
Weight loss
|
2
|
0
|
11
|
0
|
|
Myelosuppression
|
15
|
1
|
83
|
6
|
|
Neutropenia
|
14
|
0
|
78
|
0
|
|
Anemia
|
10
|
0
|
56
|
0
|
|
Thrombocytopenia
|
13
|
1
|
72
|
6
|
|
Infections (erysipelas)b
|
2
|
2
|
11
|
11
|
|
Hepatic
|
14
|
3
|
78
|
17
|
|
Elevated AST/ALT
|
13
|
2
|
72
|
11
|
|
Elevated GGT
|
13
|
2
|
72
|
11
|
|
Thyroid functionc
|
4
|
0
|
22
|
0
|
|
Depression/neuropsychiatricd
|
6
|
2
|
33
|
11
|
aOther adverse events (any grade/grade III-IV (No.)):
alkaline phosphatase (3/0), alopecia (3/0), arthralgia (4/0),
autoimmune induction/elevated ANA titer (5/0), creatine
phosphokinase (2/0), dizziness (6/0), dyspnea (1/0), erectile
dysfunction (2/0), injection side reaction (2/0), ocular/visual
(1/0), rigor/chills (2/0), rash (2/0), sicca symptoms (7/0),
sweating (5/0), taste alteration (2/0), rash (2/0).
bSevere (grade III) infections defined as infections
requiring intravenous antibiotics or hospitalization.
cHyper- and Hypothyroidism (more details are given in
the results section).
dNeuropsychiatric symtoms include anxiety and
agitation.
Table 4 Dose modification and discontinuation of
therapy
|
No.
|
%
|
|
No dose modification
|
13
|
72.2
|
|
12 month treatment
|
5
|
27.8
|
|
Discontinuation of therapy
|
8
|
44.4
|
|
because of
|
|
|
|
a) Progressive disease
|
3
|
16.7
|
|
b) Toxicitya
|
5
|
27.8
|
|
Dose modificationb
|
5
|
27.8
|
|
12 month treatment
|
4
|
22.2
|
|
Discontinuation of therapy
|
1
|
5.6
|
|
because of
|
|
|
|
a) Progressive disease
|
1
|
5.6
|
|
b) Toxicity
|
0
|
0.0
|
aReasons for discontinuation of therapy: hepatotoxicity
grade III (n = 1), depression grade III (n = 2), headache grade III
(n=1), subjective unacceptable loss of life quality causing
occupational problems (n = 1).
bReasons for dose modification: hematotoxicity grade
II (n = 1) and III (n = 1), hepatotoxicity grade II (n = 2) and III
(n = 1).
IFN-α-2a therapy: analysis of dose delivered
The mean treatment time was 8.8 ± 3.8 months (median 10.9 months).
The mean target dose being subcutaneously delivered was 6400 μg
PEG-IFN-α-2a (i.e. 89.6 ± 21% of the planned dose). Twelve months
after commencing adjuvant therapy, 12 (66.7%) of the patients had
received 91-100% of the target IFN-α-2a dose, 4 (22.2%) had
received 81-90% and 2 (11.2%) had received less than 60% of the
target dose (table 3).
Table 3 Portion of target PEG-IFN-2a dose being
delivereda
|
No.
|
%
|
|
91-100%
|
12
|
66.7
|
|
81-90
|
4
|
22.2
|
|
71-80
|
0
|
0.0
|
|
61-70
|
0
|
0.0
|
|
51-60
|
1
|
5.6
|
|
≤ 50
|
1
|
5.6
|
aMean target dose beeing delivered (all patients): 89.6
± 21%.
Dose modification and discontinuation of therapy
Dose modification resulting from toxic side effects was necessary
in 27.8% of patients (n = 5) due to hematoxicity (Grade II (n = 1)
and III (n = 1)) and to hepatotoxicity (Grade II (n = 2) and III (n
= 1)) (table 3). After reduction,
adjuvant PEG-IFN-α-2a therapy could be maintained in the majority
of the cases (n = 4) (one of whom subsequently stopped therapy due
to the recurrence of melanoma). Among the 8 patients (44.4%) who
went off-treatment, 1 had Grade III hepatic toxicity, 1 suffered
from Grade III depression, 1 had Grade III headache, and 1
discontinued therapy because she felt that she endured an
unacceptable loss of life quality causing occupational problems.
The remaining 3 patients (16.7%) had progressive disease. There
were no deaths during the treatment period (table 4).
Comparison of the most common adverse events between
PEG-IFN-α-2a and standard IFN
PEG-IFN-α-2a versus low dose standard IFN: As summarized in table 5, the percentages of patients receiving
PEG-IFN-α-2a and suffering from liver toxicity (any grade), and
myelosuppression (any grade), i.e. neutropenia, anemia, and
thrombocytopenia were significantly higher than for patients
undergoing low-dose IFN-α treatment (Fisher’s exact test; P =
0.008, P = 0.001, respectively) [23].
On the other hand, fatigue and depression were seen less
frequently in PEG-IFN-α-2a treated patients compared to a low-dose
IFN-α treated group, but did not reach statistic significance
(Fisher’s exact test; P = 0.063, and P = 0.091, respectively).
PEG-IFN-α-2a versus high dose standard IFN: PEG-IFN-α-2a
treated patients collectively experienced less frequently, fatigue
(P < 0.001), neutropenia (P < 0.068) and neuropsychiatric
(statistically not significant) adverse events compared to patients
treated with high-dose IFN-α as reported by Kirkwood and colleagues
[8], the only exception was a statistically insignificant, slightly
higher occurrence of hepatotoxicity after PEG-IFN-α-2a.
Table 5 Comparison of the most common adverse events in
different adjuvant IFN-α treatment schemes
|
- PEG-IFN-α-2a (%)
- (n = 18)
|
- Low-dose-IFN-α-2a (%)a
- (n = 322-327)
|
- High-dose-IFN-α-2b (%)b
- (n = 161)
|
|
Adverse event
|
Any Grade
|
Grade III/IV
|
Any Grade
|
Grade III/IV
|
Any Grade
|
Grade III/IV
|
|
Fatigue
|
61†
|
0†
|
81
|
1
|
96
|
21-24
|
|
Neutropenia
|
78‡
|
0†
|
45
|
0
|
92
|
26-60
|
|
Anemia
|
56‡
|
0
|
18
|
0
|
NAc
|
NA
|
|
Thrombocytopenia
|
72‡
|
6
|
15
|
0
|
NA
|
NA
|
|
Hepatic
|
78‡
|
17‡
|
35
|
2
|
63
|
14-29
|
|
Depression/neuropsychiatric
|
33
|
11
|
55
|
3
|
40
|
2-10
|
aLow-dose (3 x 3 MU IFN-α-2a/week) toxicity profile data
taken from Hancock et al, 2004 [23].
bHigh-dose toxicity profile data taken from Kirkwood
et al., 2002 [8]. When ranges were reported, the midpoint was used
for statistical comparisons c Data not available.
Discussion
This first safety analysis of pegylated interferon-alpha-2a as
adjuvant treatment for resected cutaneous melanoma revealed
myelosuppression (83%), hepatotoxicity (78%), and constitutional
side effects (78%) as the most frequently reported adverse events.
These rates for myelosuppression and liver toxicity were
significantly higher than the published rates of patients
undergoing low-dose IFN-a in low dose schemes, [23] while the
frequency of constitutional side effects were seen less frequently
in PEG-IFN-α-2a treated patients.
When PEG-IFN-α-2a (180 μg) was compared to high dose
schemes with standard IFN-α, its side effect profile became
markedly more favourable [8]. While it revealed no grade III and IV
toxicities with regard to neutropenia, anemia, fatigue, the high
dose IFN-α was reported to result in 26-60% of patients grade III
and IV toxicities with regard to neutropenia and in 21-24% with
regard to fatigue. Liver toxicity did not show significant
differences between the two IFNs and neither did depression.
In a recent Phase II dose escalation trial with weekly
PEG-IFN-α-2a monotherapy in metastatic melanoma (i.e. stage IV), an
overall tumour/tumour response rate was shown in a range similar to
the results that can be obtained by monochemotherapy, using the
standard drug dacarbazine, at the end of the 24-week study period
in the 3 dosage-defined treatment cohorts (180 μg, 360 μg, 450 μg)
[24]. However, similarly to natural IFN-α [3], a significant dose
related response of PEG-IFN-α-2a monotherapy in metastatic melanoma
could not be demonstrated [24].
With regard to efficacy in other tumours, PEG-IFN-α-2a (180
μg/wk) was similarly as effective as standard IFN-α-2a in renal
cell cancer [18, 19] and neuroendocrine gastroenteropancreatic
carcinomas [20] while PEG-IFN-α-2a (450 μg/wk) resulted in higher
response rates than standard IFN-α-2a (9 MU/day) in therapy of
chronic myelogenous leukemia [25].
The incidence and severity of many side effects have clearly
been related to the dosage, and some adverse events occur more
frequently and are more severe with a longer duration of IFN-α
therapy [26]. The 1-year course with high-dose IFN-α is associated
with significant adverse events. According to Kirkwood et al., the
majority of adult patients who underwent treatment with high-dose
IFN-α experienced toxicities, resulting in interruption, delay or
dose reduction of IFN-α in about 50% of patients [1]. Based on data
from ECOG trials, Grade III or IV toxicities secondary to fatigue,
fever, myalgia, nausea, vomiting, myelosuppression, increased
transaminases, and neuropsychiatric symptoms frequently occur
[8].
Interestingly, hepatotoxicity was experienced more frequently in
patients receiving PEG-IFN-α-2a than high-dose IFN-α (of note,
statistically not significant). The mechanisms responsible for
adverse effects on the liver, resulting in increased circulating
levels of hepatic enzymes, are poorly understood. Most likely, the
relative risk of experiencing toxicity increases proportionally
with the degree of inhibition of hepatic CYP450 isoenzyme [27, 28].
Given that more than 90% of drug metabolism in humans is dependent
on hepatic CYP450 isoenzymes, the effects of IFN-α on these enzymes
have important clinical implications with regard to potential drug
interactions [28]. There are no data yet available regarding the
impact of PEG-IFN-α-2a on the CYP450 isoenzyme systems, but
sustained presence of PEG-IFN-α may well lead to a more sustained
inhibition of CYP450 isoenzymes.
Regardless of the side effects studied, the percentage of
adverse events reported as severe (Grade III/IV) was lower with
PEG-IFN-α-2a. As the pharmacokinetic properties of low-dose IFN-α
differ substantially from those of PEG-IFN-α-2a, it is not
surprising that the proportion of patients suffering from
myelosuppression (i.e. neutropenia, anemia, and thrombocytopenia),
and liver toxicity (any Grade) was significantly higher among those
receiving PEG-IFN-α-2a than those undergoing low-dose IFN-α
treatment. Interestingly, fatigue and depression was seen less
frequently in PEG-IFN-α-2a treated patients than in the low-dose
IFN-α treated group. However the comparisons with published
low-dose and high-dose IFN-α controls must be interpreted with
caution, as our retrospective patient population was very limited.
Indeed, a recent study showed that if a lowered availability of
tryptophan and a consequent decrease of serotonergic
neurotransmission may be the mechanism underlying the
neuropsychiatric side effects of treatment with IFN-α, patients on
PEG-IFN-α are most likely to have the same risk of developing
neuropsychiatric side effects as patients on standard IFN-α
[7].
Most data on PEG-IFN-α-2a (180 μg/wk) were obtained from
patients treated for chronic hepatitis C. Here the side effect
profile is the same as that of standard IFN-α (3 MU 3 times/wk,
plus Ribavarin (1000-1200 mg/d) for 48 wk) with some difference in
frequencies between different dosages and formulations.
Hematological abnormalities (especially neutropenia) occur more
frequently in chronic hepatitis C patients treated with PEG-IFN-α
(PEG-IFN-α-2b or PEG-IFN-α-2a) than with standard IFN-α [29].
In our study there were only 2 patients with dose reduction
because of hematological toxicity (i.e. Grade III thrombocytopenia;
the other patients had only mild to moderate myelosupression). The
difference between occurrence of neutropenia in chronic hepatitis C
patients and our patients treated with PEG-IFN-α-2a may be due to
the different patient populations, with pre-existent hematological
abnormalities in chronic hepatitis C patients compared to melanoma
patients.
A considerable number of melanoma patients in our retrospective
trial developed ANAs under treatment with PEG-IFN-α-2a (27.7%);
four patients (22.2%) developed an autoimmune thyroiditis during
therapy. Elicitation of autoantibodies has been described in
patients under IFN-α therapy [30, 31] and the induction of many
autoimmune diseases has been reported in connection with the use of
this cytokine – mainly thyroiditis [32] and connective tissue
disorders such as systemic lupus erythematous (SLE) [33]. IFN-α
therapy has also been implicated in the exacerbation of other
autoimmune diseases, such as psoriasis [34] or chronic autoimmune
hepatitis [35].
The incidence of ANA developed under PEG-IFN-α-2a treatment in
our series was comparable to that under adjuvant high-dose IFN-α-2b
in melanoma patients (28% vs 26%) [36]. However, clinical signs of
autoimmune disease related to these antibodies are rare in both
groups and ANA positivity is mostly reversible after cessation of
therapy. Autoimmune thyroiditis is known to occur in treatment with
standard IFN-α [8, 37] or PEG-IFN-α-2b [37, 38]. Thyroiditis, if
undiagnosed, can cause significant problems, thus our findings of
induced autoimmunity due to PEG-IFN-α-2a treatment are of clinical
relevance. On the other hand standard IFN-induced autoimmunity has
been recognized as a parameter of immune stimulation and
effectiveness in adjuvant treatment with standard IFN-α [39].
In our study, the rate of dose reductions (27.8%) and therapy
discontinuations (27.8%) due to toxicity is somewhat higher than
the frequencies reported with 48-week PEG-IFN-α-2a in patients with
chronic hepatitis C [15, 16]. This finding might be at least
partially explained by investigators exercising particular caution
in this study, because this represented the first melanoma patient
experience with PEG-IFN-α-2a in an adjuvant stetting. Also,
detailed dose-modification schemes were not put in place. As
investigators gained more clinical experience, they were more
likely to reduce or withhold doses, rather than to discontinue
therapy. Yet, rate of dose reductions or therapy discontinuations
was still lower than for high dose standard IFN.
One question is whether the efficacy of PEG-IFN-α-2a
(180 μg) is similar to that of standard IFN-α and if it may
even be similar to that of high dose schemes with standard IFN-α –
rather than to the low dose schemes. The reason would be that, due
to its continuously high blood levels, Peg-IFN-α cannot and need
not be raised 10 fold as is done for standard IFN-α-2a in the HDI
schemes. Whether the continuous blood level of PEG-IFN-α level (180
μg) does improve disease free survival and overall survival in
patients with malignant melanoma in stage IIA to IIIB (as compared
to low-dose IFN-α treatment) cannot be addressed in this study and
is the subject of a current prospective randomized trial by the
German Society of Dermatological Oncology (ADO).
One clue that PEG-IFN-α-2a 180 μg once weekly could indeed have
an efficacy more similar to that of HDI schemes than to low dose
schemes with IFN alpha 2a (3×3 MU weekly) comes from the evaluation
of studies comparing both types of IFN in chronic hepatitis C. Here
PEG-IFN-α-2a in a dosage of 180 μg once weekly revealed a
significantly (3 to 10 fold) higher viral response rate than
IFN-α-2a (3×3 MU weekly) [22, 40].
In conclusion, prolonged treatment with PEG-IFN-α-2a in patients
with melanoma is feasible. Furthermore, tolerance was good and we
did not face any serious adverse events related to treatment. The
rate of dose reduction was substantial lower than in previous
trials with high-dose IFN-α. Drug-induced autoimmunity as a
parameter of relevant immune stimulation or surrogate marker for
monitoring the efficacy of adjuvant treatment with PEG-IFN-α-2a
warrants further evaluation.
The reduced rates of certain, e.g. dose-limiting side effects
may allow schemes equivalent to higher dosages of IFN-α than the
3×3 Mill given for low dose adjuvant therapy. This may well support
the search for more effective dosage schemes in an adjuvant
setting.
Acknowledgements
Financial support: The Department of Dermatology (Dermato-Oncology
Unit), University of Münster received financial support from
RochePharma AG Germany. Conflict of interest: None.
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