ARTICLE
Auteur(s) : Angela Funk1, Frank
Hensley2, Robert Krempien1, Dirk
Neuhof1, Michael Van Kampen3, Martina
Treiber1, Falk Roeder1, Carmen
Timke1, Klaus Herfarth1, Peter
Helmbold4, Juergen Debus1, Marc
Bischof1
1Department of Radio-oncology, University of
Heidelberg, Im Neuenheimer Feld 400, D -69120 Heidelberg,
Germany
2Department of Radio-oncology, Medical Physics,
University of Heidelberg, Germany
3Department of Radiotherapy, Nordwest Krankenhaus,
Frankfurt/ Main, Germany
4Department of Dermatology, University of Heidelberg,
Germany
accepté le 2 Janvier 2008
Cutaneous T-cell non-Hodgkin’s lymphoma accounts for
approximately 0.5-1% of all non-Hodgkin’s lymphoma (NHL) [1].
Mycosis fungoides is the most common histological subtype [2, 3].
Prognostic clinical variables are the size of the infiltrated skin
surface, lymph node involvement, and dissemination to visceral
sites [4, 5]. The rare Szézary-syndrome is a leucemic variant of
CTLC with erythroderma, lymphadenopathy and is characterized by
malignant T-cells in the circulating blood (> 40% CD4+ CD7–
T cells or CD4/CD8 ratio > 10), whereas histopathological
findings of cutaneous infiltrations correspond to Mycosis fungoides
[6, 7].
Therapeutic options for cutaneous lymphoma include topical
treatment with corticosteroids, nitrogen mustard, carmustine or
retinoids as well as systemic therapy with interferon-alpha,
chemotherapy, and extracorporal photochemotherapy, or
photochemotherapy with psoralene plus UV-A irradiation (PUVA) [5,
7, 8]. Local X-ray radiotherapy was first described 100-years ago
[9]. The technically challenging treatment of the entire cutaneous
surface was developed in the 1950s [10, 26]. Encouraging results
concerning the feasibility and efficacy of total skin electron beam
therapy (TSEBT) as a single modality treatment, especially for
patients with limited disease, have been published in the past few
decades [11-13].
Here we report a retrospective review of 18 cases of advanced
PUVA- and chemotherapy refractory cutaneous T-cell lymphoma in
stages IIB-IV treated with palliative TSEBT. Survival,
relapse, and treatment-related acute and late complications were
analyzed.
Patients and methods
Patients
From 1993 to 2004, 18 patients with advanced cutaneous T-cell
lymphoma in stages IIB-IV were treated with palliative TSEBT.
The median age of patients at presentation was 59 years (range
34-78 years). Diagnoses were established histologically
according to the WHO-EORTC classification for cutaneous lymphoma
[3]. The most common histological subtype (72%) was Mycosis
fungoides (table 1). All patients were
initially treated with chemotherapy, interferon, and/or
PUVA-photochemotherapy; none received radiotherapy. All patients
were referred to our department for TSEBT to treat multi-locular
disease progression. All patients suffered from lymphoma-associated
symptoms such as pain, itching, and ulceration. Median follow-up
was 11 months (range 0.5-46 months). The staging system
for CTCL and detailed patient characteristics are provided in tables 2 and 3.
For analysis, patients were grouped into three categories
according to the treatment result: complete response, limited
response with > 50% reduction of cutaneous lesions, and no
response.
Survival and relapse rates were calculated using the
Kaplan-Meier method from the date of radiotherapy applying
STATISTICA version 5.5 (StatSoft Inc®, USA). Treatment
related side effects were graded according to the
RTOG-classification for acute effects, and the LENT-SOMA scoring
system for late effects [14].
Table 1 Histology.
|
Histology
|
|
Mycosis fungoides
|
13 (72%)
|
|
Szézary-syndrome
|
2 (11%)
|
|
Primary cutaneous peripheral T-cell lymphoma, unspecified
|
2 (11%)
|
|
Primary cutaneous anaplastic large-cell lymphoma
|
1 (6%)
|
Table 2 TNM- and staging system for cutaneous T-cell
lymphoma (CTCL) [23].
|
TNM
|
Characteristics
|
|
T0
|
Lesions clinically and/or histopathologically suspicious
|
|
T1
|
Limited plaques, papules, or eczematous patches < 10% of skin
surface
|
|
T2
|
Generalized plaques, papules, or erythematous patches covering ≥
10% of skin surface
|
|
T3
|
Tumors
|
|
T4
|
Generalized erythroderma
|
|
N0
|
No palpable adenopathy, pathology negative for CTCL
|
|
N1
|
Palpable adenopathy, pathology negative for CTCL
|
|
N2
|
No palpable adenopathy, pathology positive for CTCL
|
|
N3
|
Palpable adenopathy, pathology positive for CTCL
|
|
M0
|
No visceral organ involvement
|
|
M1
|
Visceral involvement (pathologic confirmation)
|
|
Staging
|
T
|
N
|
M
|
|
IA
|
1
|
0
|
0
|
|
IB
|
2
|
0
|
0
|
|
IIA
|
1-2
|
1
|
0
|
|
IIB
|
3
|
0-1
|
0
|
|
III
|
4
|
0-1
|
0
|
|
IVA
|
1-4
|
2-3
|
0
|
|
IVB
|
1-4
|
0-3
|
1
|
Table 3 Patient characteristics.
|
Characteristic
|
|
Age
|
|
Median
|
59 years
|
|
Range
|
34-78 years
|
|
Sex
|
|
|
Male
|
15 (83%)
|
|
Female
|
3 (17%)
|
|
Histology
|
|
Mycosis fungoides
|
13 (72%)
|
|
Szézary-syndrome
|
2 (11%)
|
|
Other T-cell lymphoma
|
3 (17%)
|
|
Stage at presentation
|
|
IIB
|
1 (5%)
|
|
IVA
|
10 (56%)
|
|
IVB
|
7 (39%)
|
|
Radiation dose
|
|
TD > 25 Gy
|
12 (67%)
|
|
TD < 25 Gy
|
6 (33%)
|
Radiotherapy
All patients were treated with 6 MeV electrons from a linear
accelerator (Siemens KD2 linear accelerator, Concord, USA). Median
daily fractions of 1 Gy (range 1-1.5 Gy) were
administered up to a median total dose of 25 Gy (range
11-34.5 Gy). Seven patients (39%) received additional local
electron beam radiotherapy with a median dose of 30 Gy (range
24-40 Gy) due to a circumscribed relapse after the first
treatment course. One patient was treated with a second course of
TSEBT with 12 Gy (daily fractions of 1 Gy).
During TSEBT, the patient is rotated in a standing position
while being irradiated by a combination of two large electron
fields (nominally 129.5 cm × 129.5 cm at a distance of
370 cm focus to rotation axis) at gantry angles of 72.5° and
107.5° (figure 1). By
superimposing the two fields, a dose distribution with a
homogeneous range (± 10%) of 210 cm × 40 cm is
produced at the site of the patient (figure 2). The
initial electron energy of 6 MeV is reduced to approximately 3.8
MeV by a Lucite moderator of 5 mm thickness positioned between
the accelerator and the patient, and by the air along the beam
path. In this radiation field, the patient is rotated at a speed of
0.8 rounds per minute on a turntable. To minimize obscuration of
skin segments by other parts of the body, the patient stands in a
swordsman-like position. Skin regions which could not be included
in the rotation technique were irradiated with additional fixed
fields. If possible, sensitive structures like the eye lenses, the
scrotal region, and the finger and toe nails were protected with
additional lead shielding either for the complete course or for
part of the irradiation.
Results
A complete response was achieved in nine patients (50%), and a
limited response in seven patients (39%) (figures 3 and 4). Two
patients (11%) had a minimal response and died due to systemic
tumour progression and organ failure during radiotherapy.
Four patients (22%) had a continuing remission over a median
period of six months (range 2-14 months). All were treated
with TSEBT-doses ≥ 29 Gy. Twelve patients (67%) relapsed after a
median of four months (range 1-18 months), and five of these
patients were irradiated with doses of < 25 Gy. No distinct
pattern of failure, e.g. in the perineal region, was observed. The
actuarial one-year progression-free survival was 24% (figure 5). All
patients who received local re-irradiation of a circumscribed
recurrence had an excellent response, but relapsed outside the
radiotherapy treatment fields or had systemic disease progression.
The patient treated with a second course of TSEBT had a limited
response ten weeks after finishing therapy.
Lymphoma associated symptoms such as pain, pruritus, and
bleeding of ulcerated cutaneous tumours were improved in 16
patients (89%) and were unchanged in two patients (11%).
The median overall survival after the initial diagnosis of a
cutaneous lymphoma was 21 months (range 6-120 months).
The median overall survival after presentation for TSEBT was
12 months (range 0.5 to 46 months) resulting in an
actuarial one-year overall survival of 48% (figure 5).
Treatment related acute effects (grade 1 or 2)
such as erythema, desquamation, epilation, transient pruritus,
hyperkeratosis, edema, and tiredness were observed in all patients
(100%) during and directly after completing radiation therapy.
Transient grade 3 epitheliolyses was found in five patients
(28%), all with pre-existing tumour-related skin ulcerations. A
superinfection of ulcerated tumours was not observed due to regular
skin and wound care. Fifteen patients (83%) received one part of
the TSEBT course as in-patients. Fluid balance was monitored
regularly and concomitant isotonic infusions were given to avoid
exsiccation and tumour lysis syndrome.
Late effects (grade 1 and 2) such as hyper- and
depigmentation and hyperkeratosis were found in 16 patients
(89%). Hypohidrosis resulting from sweat gland loss was seen in six
patients (33%). No serious complications were associated with local
re-irradiation after TSEBT.
Discussion
Radiotherapy is highly effective in the treatment of cutaneous
lymphoma [11, 12, 15]. In our study, patients with advanced
cutaneous lymphoma in stages IIB-IV received radiotherapy for
the first time because of disease progression after extensive
pre-treatment with polychemotherapy and PUVA. An excellent
palliation was achieved with TSEBT. A complete or limited response
of advanced, partially ulcerated cutaneous lesions was seen in 89%
of patients. Commonly, radiation doses of 24-36 Gy are suggested
for TSEBT, but these doses had to be reduced in about one third of
our patients due to their advanced disease and reduced performance
status and co-morbidities [11, 13, 16]. In our study, a continuing
remission was observed only in patients who were treated with doses
≥ 29 Gy. However, the dose-response relationship in this study
must be interpreted carefully because of the small number of
patients, different tumour stages with various clinical problems,
and arbitrary selection of the dose cut-off point. Good response
rates with TSEBT did not lead to prolonged recurrence-free survival
in these patients, who had suffered from a long course of advanced
lymphoma. Most patients relapsed within one year after TSEBT. These
results are consistent with previous studies in which relapse-free
survival decreased to 5% if generalized disease was present at
radiotherapy [11, 13, 17, 18]. In contrast to palliative TSEBT for
advanced stages, radiotherapy offers a promising treatment option
in patients with less extensive disease, but no curative therapy
exists [5, 15, 19]. Five-year relapse-free survival rates of 50-75%
for stage IA and 30% for stage IB have been reported [7,
13, 20]. Additionally, TSEBT was more effective than topical
chemotherapy (e.g. mechlorethamine or BCNU) and PUVA in various
series [12, 19]. However, TSEBT can be offered only in few centres
due to the complexity of the radiotherapy technique.
The majority of patients in this study had significant relief
from lymphoma-related symptoms like pruritus, pain, and secretion
from ulcerated tumours. Acute side effects during the radiotherapy
course were transient and could be controlled without difficulty
[21-23, 25]. The grade 3 epitheliolysis observed was more
related to the pre-existing ulcerated tumours than to the radiation
dose. However, more than 80% of patients were treated as
in-patients to avoid serious complications. Haematological or
gastrointestinal toxicities were not observed due to steep dose
fall-off and the superficial effects of low-energy electrons [8,
23, 24]. For relapsed patients, a second local radiotherapy series
was effective and feasible without major toxicities.
Poor survival rates for the patients in our study can be
explained by their advanced disease stages at the time of
radiotherapy, because generalization of cutaneous tumours and
visceral and lymph node involvement are strong predictors of being
refractory to therapy, and reduced overall survival [4, 5, 7].
Randomized studies comparing TSEBT with other treatment strategies
do not exist [1, 12, 19]. Detailed recommendations for TSEBT of
stages IA-IB were published by the European Organization for
Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Group
[21]. Complete response rates of 90% are reported for irradiated
patients presenting in stage IA (limited patches and plaques) and
80% for patients in stage IB (extensive patches and plaques).
However, 10-year relapse-free survival in stage IA is 50% and in
stage IB only 10% [20, 21, 24].
Conclusion
TSEBT is a very efficient and tolerable palliative treatment for
patients with advanced cutaneous lymphoma. However, because of the
small number of patients in this retrospective study, general
treatment recommendations can not be given. If tolerated by the
patient, we currently apply doses of 30-34 Gy in fractions of
1-1.5 Gy.
Acknowledgements
Financial support: none. Conflict of interest: none.
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