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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3578-3581
Prospective Randomized Multicenter Clinical Trial on the Use of
Interferon  -2a Plus Acitretin Versus Interferon -2a Plus PUVA in
Patients With Cutaneous T-Cell Lymphoma Stages I and II
By
R. Stadler,
H.-G. Otte,
T. Luger,
B.M. Henz,
P. Kühl,
T. Zwingers, and
W. Sterry
From the Department of Dermatology, University of Ulm, Ulm, Germany;
the Department of Dermatology, Medical Center Minden, Minden, Germany;
the Department of Dermatology, University of Münster,
Münster, Germany; the Department of Dermatology, University of
Essen, Essen, Germany; the Department of Dermatology, University of
Berlin-Charité, Berlin, Germany; the Department of Dermatology,
University of Magdeburg, Magdeburg, Germany; the Department of
Dermatology, Clinic of Dortmund, Dortmund, Germany; the Department of
Dermatology, University of Heidelberg, Heidelberg, Germany; the
Department of Dermatology, University of Berlin-Benjamin Franklin,
Berlin, Germany; the Department of Dermatology, University of Zurich,
Zurich, Switzerland; the Department of Dermatology, University of
Vienna, Vienna, Austria; the Department of Dermatology,
Ferdinand-Sauerbruch-Clinic Wuppertal, Wuppertal, Germany; the
Department of Dermatology, University of Kiel, Kiel, Germany; the
Department of Dermatology, University of Göttingen,
Göttingen, Germany; the Department of Dermatology, University of
Würzburg, Würzburg, Germany; the Department of
Dermatology, St. Barbara Hospital Duisburg, Duisburg, Germany; the
Department of Dermatology, Clinic St. Georg Hamburg, Hamburg, Germany;
the Department of Dermatology, University of Greifswald, Greifswald,
Germany; the Department of Dermatology, University of Erlangen,
Erlangen, Germany; the Department of Dermatology, Clinic of Dresden,
Dresden, Germany; and the Department of Dermatology, Insel Spital Bern,
Bern, Switzerland.
 |
ABSTRACT |
Cutaneous T-cell lymphoma (CTCL) constitutes a malignant
proliferative disease involving mostly CD4+ T cells
arising in the skin. Because of the lack of curative treatment options,
interferons (IFN) have been introduced into the therapy of CTCL.
Although effective even in advanced disease, response rates were about
50% and the duration of response was short. To improve the results of
interferon monotherapy, combinations of IFN with oral photochemotherapy
(PUVA) or retinoids were investigated in nonrandomized trials showing
higher response rates. We have therefore conducted this prospective
randomized multicenter trial to compare these two combination
therapies, ie, IFN plus PUVA and IFN plus acitretin. IFN -2a
was administered at 9 MU three times weekly subcutaneously in both
groups, with lower increasing doses during the first week.
Photochemotherapy was applied after oral intake of 8-methoxypsoralen
(0.6 mg/kg body weight) 5× weekly during the first 4 weeks, 3×
weekly from weeks 5 through 23, and 2× weekly from weeks 24 through
48, with escalating doses beginning with 0.25 J/cm2.
Twenty-five milligrams of acitretin was administered daily during the
first week, and 50 mg was administered from weeks 2 through 48. Of 98 patients randomized in this study, 82 stage I and II patients were
evaluable: 40 in the IFN+PUVA group and 42 in the IFN+acitretin
group. With 70% complete remissions in the IFN+PUVA group, this
treatment was significantly superior to the IFN+acitretin group with
only 38.1% complete remissions. Time to response was significantly
shorter in the IFN+PUVA group, with 18.6 weeks compared with 21.8 weeks in the IFN+acitretin group. Side effects were mostly mild to
moderate and did not differ significantly in both treatment groups.
However, there were more adverse events leading to study
discontinuation in the IFN+acitretin group. Based on these findings,
we conclude that IFN plus oral photochemotherapy is superior to
IFN plus acitretin, inducing more complete remissions in patients
with CTCL stages I and II.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
CUTANEOUS T-CELL lymphomas (CTCL)
represent a heterogeneous group of T-cell malignancies of the skin
including classic mycosis fungoides and Sézary's syndrome as the
most common forms.1 In 1984, interferon (IFN) was
first reported to be effective in the treatment of advanced and heavily
pretreated CTCL.2 Because of high toxicity of high IFN
doses reported in this early investigation, several studies have since
been conducted with lower doses, showing IFN to be similarly
effective.3 To increase the response rates of 52% and an
average duration of response of 4 to 28 months with IFN monotherapy,
combinations of IFN with oral photochemotherapy (PUVA) or with
retinoids were introduced into the treatment of CTCL. These
combinations demonstrated higher response rates of about 96% with
IFN plus PUVA and 60% with IFN plus retinoid.3
However, these data were derived exclusively from uncontrolled
trials.4-10 To prove combination therapies including IFN as
a potentially high effective substance in the treatment of CTCL, a
prospective randomized multicenter clinical trial, in cooperation with
21 departments of dermatology in Germany, Austria, and Switzerland, was
conducted comparing the efficacy and tolerability of the combination of
IFN plus PUVA versus IFN plus retinoid (acitretin).
| |
PATIENTS AND TREATMENT |
Ninety-eight patients with histologically confirmed small to medium
sized pleomorphic T-cell lymphoma or mycosis fungoides stage I or II
were enrolled in this study. In addition, diagnoses were confirmed by
T-cell receptor rearrangement.
Staging procedures included history and physical examination, chest
x-ray, abdominal and lymph node ultrasound, complete blood count,
electrolytes, creatinine, uric acid, total bilirubin, alkaline phosphatase, lactate dehydrogenase (LDH), serum glutamate oxalacetate transaminase (SGOT), serum glutamate pyruvate transaminase
(SGPT),  -glutamyl transferase (-GT),
total serum proteins and electrophoresis, triglycerides, and total
serum cholesterol. In case of elevation, differentiation of
lipoproteins was performed.
After obtaining informed consent, the patients were randomized in a
central institution (Estimate GmbH, Ausgsburg, Germany) either to
treatment with the combination IFN -2a plus oral photochemotherapy (49 patients) or IFN -2a plus acitretin (49 patients). Treatment groups were stratified by pretreatment.
The primary study objective was the rate of complete remissions (CRs)
in both groups. Secondary study objectives were rate of partial
remissions (PRs), time to CR, tolerability of the treatments, and side
effects. Initially, 65 evaluable patients were planned in both
treatment groups, with an interim analysis after half of the patients
had been followed for at least 48 weeks, showing significantly higher
complete response rates in the IFN+PUVA group.
From the initially randomized 98 patients in this study, 6 patients did
not receive any treatment within the study, 6 patients' data were
insufficiently documented by their study centers, and 4 entries
resulted from staging errors.
Finally, 40 patients were evaluable in the IFN+PUVA group and 42 in the
IFN+acitretin group. All patients had received a minimum of 4 weeks of
treatment and photographs were taken before and after treatment.
Patients' age, duration of disease, time between last treatment and
start of the study, mode of pretreatment, and performance status were
equal in both groups. According to Bunn and Lamberg,11 stage of disease as the most important prognostic variable within this
group of mycosis fungoides or small to medium sized pleomorphic T-cell
lymphoma shows a homogeneous distribution between both treatment groups
(Table 1). There were more males (P = .007) in the IFN+acitretin group; however, no influence was found
regarding treatment result. Despite stratification, there was a higher
number of pretreated patients (P = .037) in the IFN+acitretin
group. This imbalance resulted from excluding nonevaluable patients.
In both groups, treatment was initiated with increasing doses of IFN
-2a (Roferon; Hoffmann-La Roche AG, Grenzach-Whylen, Germany) in the first week and continued with 9 MU 3 times
a week subcutaneously. Photochemotherapy was performed with oral
8-methoxypsoralen (0.6 mg/kg) 2 hours before UVA radiation 5×
weekly during weeks 1 through 4, then 3 days a week until week 23, and
2× weekly up to 48 weeks. UVA doses were started with 0.25 J/cm2, increasing up to the minimal erythema dose.
Acitretin (Neotigason; Hoffmann-La Roche AG) was
administered daily in a dosage of 25 mg during the first week and 50 mg
from weeks 2 through 48. Photochemotherapy and acitretin therapy were
performed as long as IFN treatment. Depending on tolerability,
treatment interruptions for a maximum of 2 weeks or dose adjustments
were allowed.
Duration of therapy in both treatment groups was proposed until CR
defined as no signs and symptoms of CTCL and no pathological findings
in histological examination. Maximum treatment duration was 48 weeks in
both groups. Because it was not the aim of this study to analyze time
to treatment failure or time to progression, no recommendations
concerning instructions after CR were made. Therefore, no data
answering these questions are available.
For statistical analysis of the responses, the  2 test
and multivariate logistic regression were performed. Time to events was
calculated by Kaplan-Meier methods and tested using the log-rank test.
| |
RESULTS |
With the combination IFN+PUVA, 28 of 40 (70.0%) patients achieved a
CR, with 26 of these patients in stage I and 2 in stage II disease.
This result was significantly better than the 16 of 42 (38.1%) CRs
observed in the IFN+acitretin group (Table
2). Intent to treat analysis, including all 92 patients receiving any
treatment within this study, still shows a significantly higher rate of
complete responses in the IFN+PUVA group (P < .05). The probability of success was found to be significantly increased (P = .005) by the combination of IFN+PUVA after
adjustment for pretreatment in a multivariate logistic regression.
PRs were seen in 4 patients with IFN+PUVA therapy and in 9 patients
with IFN+acitretin therapy. Overall response (CRs+PRs) was 80.0% in
the IFN+PUVA group and 59.5% in the IFN+acitretin group. Time to CR
was significantly shorter in the IFN+PUVA group with 18.6 weeks versus
21.8 weeks in the IFN+acitretin group (P = .0015). In addition,
time to response (CRs+PRs) was significantly shorter (10.9 weeks) in
the IFN+PUVA group compared with 12.6 weeks in the IFN+acitretin group
(P = .026; Table 2). However, these data may be of less
importance for patients' treatment.
Total IFN dose was similar in both treatment groups, with 569 and 609 MU, respectively, showing no difference in patients responding with CR
(569 MU) or not (611 MU). Mean cumulative acitretin dose was 6,556 mg
and was lower in the responding patients with 5,962 versus 6,927 mg in
the nonresponding patients. Total PUVA dose was 139 J/cm2
in a total of 58.5 treatment days, with responding patients receiving 158.6 J/cm2 in 61.2 days versus 94.8 J/cm2 in
51.5 days in patients failing to show a complete response (Table 3).
Life-threatening adverse events were not observed in either treatment
group. Mild and moderate (World Health Organization [WHO] grade 1 and
2) adverse events were seen in 55.0% of the IFN+PUVA group and in
52.4% of the IFN+acitretin patients. Most common were flu-like
symptoms, and less frequent were reductions of red and/or white
blood counts and gastrointestinal disorders and elevations of
triglycerides (retinoid group) and liver enzymes. In some patients,
dryness of the skin, hair loss, and neurologic or psychiatric symptoms
were observed (Table 4). Four (10.0%) patients of the IFN+PUVA group and 13 (31.0%) of the IFN+acitretin group developed severe side effects (WHO grade 3). Most adverse events
could be managed satisfactorily by adjusting doses, although 2 patients
of the IFN+PUVA and 9 of the IFN+acitretin group had to be withdrawn
from the study.
Determination of neutralizing IFN antibodies, performed in
all patients before, during, and after treatment, showed no
correlation between the development of antibodies, the treatment
group, and the response. In fact, 3 patients with high
neutralizing antibodies in the IFN+PUVA group were responders.
| |
DISCUSSION |
CTCLs represent a heterogeneous group of malignant diseases arising
mostly from CD4+ T cells in the skin, including mycosis
fungoides, Sézary's syndrome, pleomorphic T-cell lymphoma, and
other, more rare entities.1 A number of treatment options,
such as oral photochemotherapy, total skin electron beam, topically
applied cytotoxic substances, or systemic chemotherapy, are available,
although none of them has been proven to be curative.12
Therefore, new agents, such as IFNs and retinoids, have been introduced
into the treatment of CTCL. IFN has been shown to be effective even
in advanced and heavily pretreated patients,2 with an
overall response rate in the most important studies not exceeding
52%.3 To improve these results, combinations of IFN
with PUVA or retinoids were investigated, but only in small
nonrandomized trials.4-10 To prove combination therapies
containing IFN as an effective substance in the treatment of CTCL,
we conducted this prospective randomized multicenter trial to compare
the combination of IFN -2a plus PUVA with that of IFN -2a plus
acitretin.
Our results within the IFN+PUVA group show similar complete response
rates (70%) to those published by Kuzel et al4 (62%) and
the 73% observed by us in an earlier study,5 despite
differences in patient selection and maximum dose of IFN. The number
of partial responses is lower in our study, resulting in an overall
response rate of only 80%, compared with 90% by Kuzel et
al.4
In comparison, complete response results with photochemotherapy alone
are varying between 40% and 100% in several retrospective studies
concerning stage I and II disease.13
The results with the IFN+acitretin treatment must be compared with
publications on the combination of IFN and etretinate, because
acitretin is the main active metabolite of etretinate and has been
substituted for etretinate on the market for safety reasons. With
38.1%, we reached a better complete response rate than Dreno et
al,6 who treated 26 patients with 9 MU IFN plus 0.5 mg/kg body weight etretinate, and in comparison to results of
Thestrup-Pedersen et al,7 who used 18 MU IFN and 0.7 mg/kg body weight etretinate in 7 patients. In contrast to our study, these investigators included patients with advanced CTCL stages III and
IV, which might explain the differences in response rates. Braathen and
McFadden10 reached 50% CR, although in only a small number
of patients. Our response rate of 59.5% is similar to data published
by others.3
For retinoids such as etretinate, 13 cis-retinoic acid, and
arotinoid-ethylesther as monotherapy, complete response rates between
12% and 30% are published.3
Because the mean total IFN dose of 569 MU for IFN+PUVA versus 609 MU
for IFN+acitretin was similar in both treatment groups, the difference
in response between these two groups cannot depend on the IFN dose.
Within the IFN+acitretin group, total IFN and acitretin doses were
similar in patients with complete or no CR, giving evidence that CR
seems not to be dependent on these variables. In the IFN+PUVA group,
there was a difference in total PUVA dose comparing patients with
complete and no CR, but an influence of this difference on the outcome
of the present study could not be determined.
In contrast to the report of Kuzel et al,4 we observed high
titers of neutralizing anti-IFN antibodies in 3 patients, contradicting their statement that immunosuppressive effects of PUVA therapy might
prevent the development of anti-IFN antibodies. Furthermore, the
present data speak against an impact of neutralizing anti-IFN antibodies on the treatment results in CTCL patients, as suggested by
Rajan et al.14
In conclusion, IFN plus PUVA is superior compared with IFN plus
acitretin in the induction of CR in patients with CTCL stages I and II.
In addition, response was reached earlier and side effects seemed to be
comparable, with slight advantages in favor of IFN+PUVA treatment.
The role of IFN in combination with PUVA is currently evaluated in a
randomized controlled study with IFN+PUVA versus PUVA alone.
| |
FOOTNOTES |
Submitted February 17, 1998;
accepted July 8, 1998.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Prof R. Stadler, MD, Department of
Dermatology, Medical Center Minden, Academic Teaching Unit, University
Münster, Portastr. 7-9, 32423 Minden, Germany.
| |
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Top
Abstract
Introduction
1