Int. J. Radiation Oncology Biol. Phys., Vol. 74, No. 1, pp.

154–158, 2009
Copyright Ó 2009 Elsevier Inc.
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doi:10.1016/j.ijrobp.2008.06.1918

CLINICAL INVESTIGATION Lymphoma

LOW-DOSE PALLIATIVE RADIOTHERAPY FOR CUTANEOUS B- AND

T-CELL LYMPHOMAS

KAREN J. NEELIS, M.D., PH.D.,* ERIK C. SCHIMMEL, M.D.,y MAARTEN H. VERMEER, M.D., PH.D.,z
NANCY J. SENFF, M.D.,z REIN WILLEMZE, M.D., PH.D.,z AND EVERT M. NOORDIJK, M.D., PH.D.*
From the Departments of *Clinical Oncology and z Dermatology, Leiden University Medical Center, Leiden, The Netherlands;
and y Department of Radiotherapy, Radiotherapeutical Institute Arnhem, Arnhem, The Netherlands

Purpose: To determine the efficacy of low-dose palliative radiotherapy for both low-grade malignant cutaneous
B-cell lymphomas (CBCLs) and cutaneous T-cell lymphomas (mycosis fungoides).
Methods and Materials: A total of 18 patients with low-grade CBCL (10 primary cutaneous marginal zone B-cell
and 8 primary cutaneous follicle center lymphomas) with 44 symptomatic plaques and tumors underwent low-dose
(4 Gy in two fractions) local radiotherapy. A total of 31 patients with mycosis fungoides were treated at 82 symp-
tomatic sites, initially with 4 Gy and later with 8 Gy in two fractions.
Results: The complete response rate for CBCL lesions was 72%. Of the 44 B-cell lymphoma lesions, 13 were re-
treated to the same site after a median of 6.3 months because of persistent (n = 8) or recurrent (n = 5) symptomatic
disease. Of the mycosis fungoides patients treated with 4 Gy in two fractions (17 lesions), 70% failed to respond.
Increasing the dose to 8 Gy in two fractions yielded a complete response rate of 92% (60 of 65 lesions). The patients
in whom low-dose radiotherapy failed were retreated with 20 Gy in eight fractions.
Conclusion: Our results have demonstrated that low-dose involved-field radiotherapy induces a high response rate
in both CBCL and cutaneous T-cell lymphoma lesions without any toxicity. Therefore, this treatment is now our
standard palliative treatment. At progression, it is safe and feasible to apply greater radiation doses. Ó 2009
Elsevier Inc.

Low-dose radiotherapy, Mycosis fungoides, Cutaneous lymphoma, Low-grade lymphoma.

INTRODUCTION
Primary cutaneous lymphomas are rare, with an estimated an-
nual incidence of 1:100,000 (1–3). As a group, they have
a heterogeneous clinical behavior, often quite different
from their nodal counterparts. According to the combination
of clinical, histologic, immunophenotypical, and genetic fea-
tures, different types of cutaneous B-cell lymphomas
(CBCLs) and cutaneous T-cell lymphomas (CTCLs) can be
distinguished (3, 4). CTCLs are much more common and rep-
resent approximately 75% of all primary cutaneous lympho-
mas. The different types of primary cutaneous lymphoma
included in the new World Health Organization–European
Organization Research and Treatment of Cancer consensus
classification for cutaneous lymphomas are presented in
Table 1.
The treatment of cutaneous lymphoma depends on the dis-
ease type, disease stage at diagnosis, and the extent of skin
involvement (3). A powerful treatment option for CBCL is
radiotherapy (RT), which can be given with either curative
or palliative intention, often with good results (5–9). In recent
years, several studies have been published on the use of low-
dose involved-field RT for low-grade lymphomas of nodal
origin reporting significant percentages of response with
a median time to local progression of approximately 2 years
(10–15). This strategy is interesting, because it would mean
a nontoxic treatment achieved with minimal patient effort
and the potential to reduce costs. Although cutaneous lym-
phomas behave differently from their systemic counterparts
in terms of clinical presentation and the reaction to treatment,
we thought it worthwhile to investigate a similar approach for
patients with a (low-grade) cutaneous lymphoma for whom
no curative treatment was available.
Mycosis fungoides (MF) is the most frequent type of
CTCL and is also frequently treated with RT (16). Despite lo-
cal treatments consisting of topical steroids, topical applica-
tion of nitrogen mustard or chlormustine and psoralen plus
ultraviolet A (PUVA), many patients continue to develop
new patches and plaques for which local RT is often required
for symptom control. However, treatment with RT is limited
by the cumulative skin toxicity, especially because many

Reprint requests to: Karen J. Neelis, M.D., Ph.D., Department of
Clinical Oncology, K1-P, Leiden University Medical Center, P.O.
Box 9600, Leiden 2300 RC The Netherlands. Tel: (+31) 71-526-
1990; Fax: (+31) 71-526-6760; E-mail: k.j.neelis@lumc.nl
154
Conflict of interest: none.
Received April 11, 2008, and in revised form June 6, 2008.
Accepted for publication June 9, 2008.
 Low-dose RT for cutaneous lymphomas d K. J. NEELIS et al. 155

Table 1. WHO-EORTC classification of cutaneous Table 2. Patient characteristics

lymphomas
Characteristic MF CBCL
Cutaneous B-cell lymphomas
Primary cutaneous marginal zone B-cell lymphoma Gender
Primary cutaneous follicle centre lymphoma Male 21 (68) 10 (62)
Primary cutaneous diffuse large B-cell lymphoma, leg type Female 10 (32) 8 (38)
Primary cutaneous diffuse lager B-cell lymphoma, other Age (y)
Cutaneous T-cell and natural killer-cell lymphomas Median 64 55
Mycosis fungoides Range 38–83 24–87
MF variants and subtypes Lymphoma type
Folliculotropic MF PCFCL 0 8
Pagetoid reticulosis PCMZL 0 10
Granulomatous slack skin MF 31 0
Sézary syndrome Fields treated per patient (n)
Adult T-cell leukemia/lymphoma Median 2 2
Primary cutaneous CD30+ lymphoproliferative disorders Range 1–8 1–9
Primary cutaneous anaplastic large cell lymphoma Treated lesion characteristics
Lymphomatiod papulosis Size (cm)
Subcutaneous panniculitis-like T-cell lymphoma Median 4 2
Extranodal natural killer/T-cell lymphoma, nasal type Range 1–20 1–10
Primary cutaneous peripheral T-cell lymphoma, unspecified Thickness (%)
Primary cutaneous aggressive epidermotropic CD8+ T-cell #1 cm 60 91
lymphoma (provisional) $1 cm 40 9
Cutaneous g/d T-cell lymphoma (provisional) Follow-up duration (mo)
Primary cutaneous CD4+ small/medium-size pleomorphic T-cell Mean 9.6 13.3
lymphoma (provisional) Range 1–42 2.3–42
Precursor hematologic neoplasm
CD4+/CD56+ hematodermic neoplasm (blastic natural killer-cell Abbreviations: MF = mycosis fungoides; CBCL = cutaneous
lymphoma) B-cell lymphoma; PCFCL = primary cutaneous follicle center
lymphoma; PCMZL = primary cutaneous marginal zone lymphoma.
Abbreviations: WHO = World Health Organization; EORTC =
European Organization for Research and Treatment of Cancer;
MF = mycosis fungoides. Most patients were referred from the Department of Dermatology,
This research was originally published in Blood. Willemze R, and the decision to use 2  2 Gy palliative treatment was made in
Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous a multidisciplinary outpatient clinic.
lymphomas. Blood. 2005;105:3768–3785. Ó American Society of Low-dose RT was offered to MF patients with plaques or tumor-
Hematology. ous plaques resistant to treatment with steroids and/or PUVA. The
initial treatment in patients with low-grade CBCL was with curative
patients with MF undergo total skin irradiation for disease intent (i.e., 30 Gy in 15 fractions) in the case of a solitary lesion or
management. To date, all reports of low-dose involved-field several lesions in proximity to each other that could be treated in the
RT have been of patients with a lymphoma of B-cell origin. same RT field. All other cases and recurrences were treated with
low-dose palliative RT. The number of fields treated simultaneously
Whether a similar low-dose RT schedule could be applied to
was one to four.
palliate symptoms for patients with CTCL is unknown. In
this report, we describe our results, including the response
Methods
rates and response duration and toxicity, of palliative The RT regimen consisted of 4 Gy, prescribed at the maximal
low-dose local RT for low-grade CBCL and MF. dose, in two fractions given within 2–4 days. Because the results
of this treatment regimen for the first 9 patients with MF were dis-
appointing, we decided to increase the fraction dose for this group
METHODS AND MATERIALS
from 4 Gy to a total dose of 8 Gy from October 2002 onward.
Patients All lesions were photographed with the designed field borders to fa-
Between February 2002 and March 2007, we treated 49 patients at cilitate the response assessment after RT, the size of the lesion was
126 different lymphoma sites. This group comprised 18 patients with measured, and the thickness estimated. Treatment was directed at the
low-grade CBCL (10 primary cutaneous marginal zone lymphoma visible lesion with a margin of 2 cm of surrounding healthy-looking
[PCMZL]) and 8 primary cutaneous follicle center lymphoma skin with an electron beam of appropriate energy (mostly 4 MeV).
[PCFCL]) and 31 patients with MF (Table 2). The diagnosis was de- The response assessment was done in the outpatient clinic 4–6
termined using the criteria of the World Health Organization-Euro- weeks after irradiation. Follow-up visits were usually scheduled ev-
pean Organization for Research and Treatment of Cancer ery 3–4 months. A complete response (CR) was defined as a com-
classification and confirmed in consensus meetings of the Dutch Cu- plete disappearance of the lesion and symptoms involved, partial
taneous Lymphoma Working Group. All patients with MF had been response (PR) as >50% regression of the lesion, stable disease,
previously treated with topical steroids and/or PUVA but were and progressive disease were grouped together as ‘‘no response.’’
deemed to have disease refractory to this regimen for at least the region
of skin considered for RT. Of the 31 MF patients, 15 also had under- Statistical analysis
gone total skin irradiation before the current local treatment (on aver- In the statistical analysis of treatment efficacy, the irradiated fields
age, 2.5 years before the current irradiation, 35 Gy in 20 fractions). were considered independent from each other. The time to
156 I. J. Radiation Oncology d Biology d Physics
retreatment was calculated using the Kaplan-Meier method. The pri-
mary endpoint was response duration for the irradiated site, and
failure was defined as the persistence of symptoms requiring retreat-
ment or retreatment for disease recurrence after reaching a CR. Pa-
tients who died were censored at death. Follow-up for each site was
calculated from the date of the first fraction to the day of the first re-
irradiation or the last follow-up visit. Differences in the response rate
between superficial (#1 cm) and thicker lesions and between
smaller and larger lesions (median size was used as the cutoff)
were tested using Fisher’s exact test.
RESULTS
Cutaneous B cell lymphoma
A total of 18 patients with CBCL underwent treatment for
44 different nodules and plaques. Of these 44 lesions, 33
(75%) reached a CR. All CRs were documented at the first
follow-up visit 4–6 weeks after RT and reported by the pa-
tients to have happened within a couple of days. Five lesions
had a PR and another six remained stable. Four patients had
a mixed response, developing a CR in one irradiated lesion
with another remaining stable. The overall response rate
(CR+PR) was very high (86%). No difference in response
was observed for patients with a PCFCL and PCMZL.
The size and thickness of the lesion also did not influence
the response rate. Of the 40 lesions, 30 (75%) with a thickness
#1 cm and 3 (75%) of the 4 lesions >1 cm reached a CR (p =
1.0). Of the 23 lesions, 18 (78%) with a size #2 cm and 15
(71%) of the 21 lesions >2 cm reached a CR (p = 0.73).
Thirteen lesions were retreated, five for true recurrences,
on average 10 months (range, 2.3–24.4) after the initial RT,
which yielded a rapid CR. The other eight retreatments (in
5 patients) were performed for persistent complaints, mainly
itching or cosmesis. For reirradiation, we always used our
conventional dose fractionation scheme of 20 Gy in eight
fractions. The actuarial time to retreatment is shown in
Fig. 1. The median follow-up duration of all treated CBCL
lesions was 13 months (range, 2.3–42).
1,0
proportion free from
0,8
retreatment
0,6
0,4
0,2
0,0
0 6 12 18 24 30 36 42
time (months)
Fig. 1. Actuarial proportion free of retreatment for 44 low-grade
CBCL lesions treated with low-dose palliative radiotherapy
(2  2 Gy).
Volume 74, Number 1, 2009
Cutaneous T-cell lymphoma, mycosis fungoides
Between February 2002 and August 2002, 17 MF lesions
in 9 patients were irradiated with 2  2 Gy with disappointing
results. Of the 17 lesions, 12 (70%) failed to achieve a CR
within 2 months after RT. Of the 17 fields, 11 were reirradi-
ated with a greater dose (20 Gy in eight fractions) at a rela-
tively short interval after the first irradiation because of
persistence of the lesion and symptoms; none of the patients
had progressive disease. Retreatment with 20 Gy yielded
a rapid CR in all patients.
We decided to increase the radiation dose for the subse-
quent MF patients to 2  4 Gy. We treated 65 plaques or tu-
mors in 24 patients, for a CR rate of 92% (60 of 65 lesions),
a PR in 4 lesions, and stable disease in 1. Of the 39 lesions, 35
(90%) with a thickness of #1 cm and 25 (96%) of the 26
lesions >1 cm reached a CR (p = 0.34). Of the 37 lesions,
36 (97%) with a size of #4 cm and 24 (86%) of the 28 lesions
>4 cm reached a CR (p = 0.16).
Of those 65 lesions, 5 were reirradiated, 3 after a previous
CR and 2 for progression after a PR. The actuarial results for
these treatment regimens are shown in Fig. 2. The average
follow-up duration for all treated MF lesions was 9.6 months
(range, 1.1–41.8; median, 5.3).
Toxicity
We did not see any side effects from these low radiation
doses to the skin. An interesting finding was that 2  2 Gy
can still cause temporary hair loss in the irradiated areas in
some patients.
DISCUSSION
In this report, we have documented a high rate of induced
remissions using low-dose palliative RT for low-grade cuta-
neous lymphomas. It has been well documented that local RT
is effective to control cutaneous lymphomas. For low-grade
CBCL such as PCFCL and PCMZL, doses #30–40 Gy are
used as the primary treatment for single disease locations at
1,0
proportion free from
0,8
retreatment
0,6
0,4
0,2
0,0
0 6 12 18 24 30 36 42
time (months)
Fig. 2. Actuarial proportion free of retreatment for MF lesions
treated with low-dose palliative radiotherapy (2 x 4 Gy, n = 65
[upper curve] and 2  2 Gy, n = 17 [lower curve]).
 Low-dose RT for cutaneous lymphomas d K. J. NEELIS et al.
presentation in an attempt to control the disease on a long-
term basis. However, relapses out of field are quite common,
in particular for PCMZL (17, 18), and in this case, the disease
is regarded as incurable, and palliative RT is offered to con-
trol symptoms (3, 6, 9, 19, 20).
Low-dose involved-field RT is a well-documented ap-
proach for non-Hodgkin’s lymphoma of nodal origin (10,
11, 15). The report by Johannsson et al. (11) also included ex-
tranodal sites, including 9 patients with skin involvement; all
reported to achieve a CR. The series reported by Girinsky
et al. (15) contained 26 extranodal sites, possibly also involv-
ing skin. The complete remission rate was greater for extra-
nodal sites (69%) than for nodal sites (55%), but the
response of the skin lesions was not reported separately.
Our results for patients with a CBCL are in agreement with
those for nodal follicular lymphoma patients.
In contrast to the systemic non-Hodgkin’s lymphoma
group, of which T-cell lymphomas are only a small subset
with a much more aggressive clinical course, the cutaneous
lymphoma population contains a much larger number of pa-
tients with T-cell lymphoma (75%), mostly MF patients. In
itself, this is still a heterogeneous group of patients, some
with an ‘‘indolent’’ disease course and others (approximately
20% of MF patients) in whom disease progression is more
rapid and the skin involvement is more pronounced. Many
patients with MF receive RT at some time during their illness.
This is either done for diffuse skin infiltration that is refrac-
tory to PUVA, in which case, total skin RT is used, or as local
treatment for localized relapses after either total skin RT or
PUVA. In the past, we used doses of 20 Gy for these locali-
zations, 8  2.5 Gy, four times weekly. Although this frac-
tionation scheme is usually well tolerated, it results in
a considerable burden for the patients and the department
in terms of the number of hospital visits necessary. The cu-
mulative dose to the skin might become substantial in the
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