REPORTS

Guidelines for phototherapy of mycosis fungoides

zary syndrome: A consensus statement of the
and Se
United States Cutaneous Lymphoma Consortium
Elise A. Olsen, MD,a Emilia Hodak, MD,b Thomas Anderson, MD,c Joi B. Carter, MD,d
Marsha Henderson, MD,e Kevin Cooper, MD,f and Henry W. Lim, MDe
Durham, North Carolina; Tel Aviv, Israel; Ann Arbor and Detroit, Michigan;
Boston, Massachusetts; and Cleveland, Ohio

Background: Ultraviolet light (UVL) is a long established treatment for mycosis fungoides (MF) and
S
ezary syndrome (SS), subtypes of cutaneous T-cell lymphoma (CTCL). Treatments have traditionally
included broadband, narrowband ultraviolet B light (UVB) and psoralen plus ultraviolet A light
photochemotherapy (PUVA), but more recently, treatment options have expanded to include UVA1 and
excimer laser. UVL is used either as monotherapy or as an adjuvant to systemic therapy, demonstrating
efficacy in many cases that equal or surpass systemic medications. Despite its utility and duration of use, the
current practice of using UVL guidelines for psoriasis to treat patients with MF/SS is problematic because
the goals of prolonging survival and preventing disease progression are unique to CTCL compared to
psoriasis.

Objectives: We sought to develop separate guidelines for phototherapy for MF/SS for both clinical practice
and for clinical trials.

Methods: Literature review and cutaneous lymphoma expert consensus group recommendations.

Results: This paper reviews the published literature for UVB and UVA/PUVA in MF/SS and suggests
practical standardized guidelines for their use.

Limitations: New standardization of phototherapy.

Conclusions: These guidelines should allow the comparison of results with phototherapy in MF/SS
across different stages of patients, centers, and in combination with other agents in practice and in clinical
trials. ( J Am Acad Dermatol http://dx.doi.org/10.1016/j.jaad.2015.09.033.)

Key words: cutaneous T-cell lymphoma; phototherapy; PUVA; mycosis fungicides; NB-UVB;
S
ezary syndrome; UVL.

From the Departments of Dermatology and Medicine,a Duke
University Medical Center, Durham; Department of Dermatolo-
gy,b Rabin Medical Center, Beilinson Hospital, Sackler Faculty of
Medicine, Tel Aviv University; Department of Dermatology,c
University of Michigan, Ann Arbor; Department of Dermatolo-
gy,d Massachusetts General Hospital, Boston; Department of
Dermatology,e Henry Ford Hospital, Detroit; and Department of
Dermatology,f Case Western Reserve University, Cleveland.
Funding sources: None.
Dr Olsen is on the advisory board of and is consultant for Actelion.
Dr Anderson is an investigator for Eisai. Dr Cooper is an
investigator for Estee Lauder and LOreal, a consultant for
Anacor, Avon, GSK, and Takeda, and the Vice President of
Fluence Therapeutics. Dr Lim is an investigator for Clinuvel and
Estee Lauder and a consultant for Clinuvel, Estee Lauder,
Ferndale, La Roche-Posay, Palatin, Pierre Fabre, and Uriage.
The other authors have no conflicts of interest to declare.
These guidelines were developed specifically by members of the
United States Cutaneous Lymphoma Consortium based on the
need for education and standardization of phototherapy
treatment for mycosis fungoides and S
ezary syndrome without
relevant conflicts of interest by authors and without outside
support. Nonetheless, they should not be considered to be
sponsored or endorsed by the American Academy of Derma-
tology because they were not prepared under the American
Academy of Dermatology guidelines.
Reprints not available from the authors.
Correspondence to: Elise A. Olsen, MD, Box 3294, Duke University
Medical Center, Durham, NC 27710. E-mail: elise.olsen@dm.
duke.edu.
Published online November 4, 2015.
0190-9622/$36.00
2015 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2015.09.033

1
2 Olsen et al J AM ACAD DERMATOL
n 2015

INTRODUCTION and ultraviolet C (UVC) as 10 to 280 nm.1 However,

Background the convention in photobiology has been to divide
Ultraviolet light (UVL)ebased therapy, specif- UVL into subcategories based on biologic effect (ie,
ically, ultraviolet B light (UVB) phototherapy and UVA, 320-400 nm; UVB, 290-320 nm; and UVC,
psoralen plus ultraviolet A light (PUVA) photoche- 200-290 nm).2-4 Because UVC is absorbed in the
motherapy, has been a mainstay of treatment of atmosphere, the clinically relevant electromagnetic
mycosis fungoides (MF) for the past 50 years. radiation emitted by the sun as it reaches the surface
Initially, it was used exclu- of the earth consists of UVB
sively as monotherapy, but (5%) and UVA (95%).3
more recently it has been CAPSULE SUMMARY Because of its biologic
commonly used as part of a properties, UVA is further
d There are no disease-specific guidelines
multimodality therapeutic subdivided into UVA1 (340-
for phototherapy used to treat mycosis
regimen. Its efficacy is 400 nm) and UVA2 (320-
fungoides and S
ezary syndrome (MF/SS)
beyond dispute, but how to 340 nm). The biologic effect
despite the fact that efficacy in many
best harness this while mini- of shorter wavelength UVA2
cases equals or surpasses that of
mizing side effects has yet to is closer to UVB (ie, it is more
systemic medications.
be fully determined. likely to induce erythema
The United States d This paper reviews the published than tanning). UVA1 is now
Cutaneous Lymphoma Con- literature for safety and efficacy of UVB used to treat various skin
sortium (USCLC) is a and UVA/PUVA in MF/SS and suggests conditions, including MF.5
multidisciplinary group of standardized guidelines for their use. Broadband UVB (BB-
physicians whose mission is d These guidelines should enhance patient UVB) units available in clin-
to advance the care of care and allow the comparison of results ical practice emit broadly
patients with cutaneous lym- with phototherapy in MF/SS across sites between 270 and 390 nm,
phoma, either through the and studies. with a peak at 313 nm.
establishment of standards Narrowband UVB (NB-UVB)
for clinical care or clinical refers to a radiation source
research or through collaborative basic or clinical with a sharp emission peak between 311 and 312 nm.
research. This paper reviews the literature on the Although BB-UVB therapy was widely used in the
efficacy and safety of the various types of UVL used past, currently the vast majority of UVB therapy
to treat MF and its leukemic counterpart, S
ezary delivered around the world is in the form of NB-UVB.
syndrome (SS), and with the addition of expert There are other forms of phototherapy. The
opinion, the USCLC hopes to accomplish the excimer xenon chloride laser emits at 308 nm.6 In
following: addition, the combination of psoralen, which sensi-
a. Develop standardized guidelines for photo- tizes the patient to UVA, followed by UVA exposure is
therapy, including photochemotherapy, of MF/ a form of photochemotherapy referred to by the
SS patients seen in practice settings acronym PUVA. For the purposes of our discussion,
b. Enable the capture and analysis of accurate we will include photochemotherapy under the um-
efficacy data on phototherapy in MF/SS at mul- brella of the term phototherapy. Phototherapy with
tiple sites through standardization of treatment BB-UVB, NB-UVB, UVA1, PUVA, BB-UVA, and the
c. Accurately attribute and track side effects of excimer laser have all demonstrated efficacy in the
phototherapy in MF/SS using standardized treat- treatment of MF.
ment protocols The effect of UVL, either as monotherapy or
d. Narrow the variables of phototherapy used in adjuvant therapy, on the various stages of MF/SS, is
clinical trials of MF to allow collation of results multifactorial and is different for UVB and UVA.
between centers and comparison of results For a given dose, UVB at 300 nm is approximately
across sites and studies 1000-fold more erythemogenic compared to UVA at
e. Assist in the development of clinical performance 360 nm.4 However, because of its shorter wave-
measures in MF/SS length, UVB is primarily absorbed in the epidermis
with less ability to penetrate beyond it compared to
UVA.4,7 Therefore, the primary direct effects of UVB
Types of UVL are on the epidermal keratinocytes, Langerhans cells
The International Congress on Light in 1932 (LCs), follicular infundibulum, and any cells in
defined the components of UVL as follows: ultravi- the upper dermis, including lymphocytes. In contra-
olet A (UVA) as 315 to 400 nm, UVB as 280 to 315 nm, distinction, UVA, particularly UVA1, is able to
J AM ACAD DERMATOL Olsen et al 3
VOLUME jj, NUMBER j

cutaneous T-cell lymphoma (CTCL), and mycosis

Abbreviations used:
fungoides. Publications in English of either BB-UVB
BB-UVB: broadband ultraviolet B light or NB-UVB with [5 patients and with adequate
CCR: complete clinical response
CR: complete response information on methodology were selected for
IFN: interferon review.9-29 In the event that a follow-up paper of
MED: minimal erythema dose an initial cohort of patients was published and clearly
MF: mycosis fungoides
MOP: methoxypsoralen gave information on the preceding patients, only the
MPD: minimal phototoxic dose most recent paper was included. Information
NB-UVB: narrowband ultraviolet B light regarding side effects was extracted from the original
PUVA: psoralen plus ultraviolet A light
photochemotherapy studies using UVB phototherapy for MF and
RFI: relapse-free interval considered in conjunction with a review of recent
SCC: squamous cell carcinoma literature on the safety of UVB for all cutaneous
SS: S
ezary syndrome
TSEB: total skin electron beam disorders. Any adjuvant treatment delivered topically
USCLC: United States Cutaneous Lymphoma to sites unexposed to the phototherapy was not
Consortium factored in, because the majority of studies did not
UVA: ultraviolet A light
UVB: ultraviolet B light report on this. If systemic agents were also used,
UVC: ultraviolet C light these patients were excluded from the phototherapy
UVL: ultraviolet light monotherapy analysis.
UVR: ultraviolet radiation
The papers were judged using a modification of
the US Preventive Services Task Force guidelines for
evidence-based medicine,30 as follows: Level I
penetrate the entire dermis and possibly the subcu- evidence is obtained from at least one properly
taneous tissue7; therefore, in addition to those randomized controlled trial; level II-1 is evidence
structures affected by UVB, UVA is able to directly obtained from at least one well-designed controlled
affect lymphocytes in the deep dermis as well as trial without randomization; level II-2 is evidence
fibroblasts, dermal dendritic cells, mast cells, obtained from at least one prospective, well-
endothelial cells, macrophages, and deeper parts of designed cohort or case-control study, preferably
the follicular apparatus.2,8 from more than one center or research group; level
Specific recommendations for treatment and tools II-3 is evidence obtained from at least one retro-
to aid patients begin in the section entitled spective, well-designed cohort or case-control study,
Recommendations for phototherapy of MF/SS. preferably from more than one center or research
group; level III is evidence obtained from multiple
UVB PHOTOTHERAPY IN MF/SS: time series with or without the intervention; and
CLINICAL OUTCOMES level IV evidence includes opinions of respected
Overview authorities, based on clinical experience, descriptive
UVB phototherapy, including BB-UVB and studies, and case reports or reports of expert
NB-UVB, have been used since at least 1982 and committees.
1999, respectively, for the treatment of MF.9,10 The
relatively low incidence of MF and previous lack of Efficacy of broadband UVB (level of evidence
standardized guidelines for therapy in MF have led to II-3)
a dearth of appropriately powered, randomized, We note 4 published studies on the use of BB-UVB
controlled trials and have made evidence-based to treat MF,9,14-16 3 of which included home UVB
treatment of MF a daily clinical challenge. Many of therapy with 2 of the 3 reports on the same patients.
the current treatment recommendations for The 3 nonoverlapping studies included a cumulative
phototherapy in MF are based on small studies, total of 109 patients and included predominantly
case series, or expert opinion. This review of the patients with stage IA and IB MF, although there was
published literature on UVB phototherapy for MF no mention of whether adenopathy was present or
provides the opportunity to address the question of not in 1 study.15 The clinical response (CR) rates
efficacy and safety of this treatment modality. were similar for stage IA or patch-only stage disease,
and had a much higher rate of CR (83-89%) than
Methods either stage 1B or plaque-stage disease (0-50%). The
A PubMed review of published data on UVB treatment regimens included daily phototherapy for
phototherapy for treatment of MF was performed home BB-UVB, while office treatments were 3 times
using the following search terms: broadband, per week. All regimens were continued until
narrowband, phototherapy, ultraviolet therapy, clearance with a higher cumulative UVL dose needed
4 Olsen et al
to achieve response in comparable patients treated
with NB-UVB than BB-UVB, a function of the fact
that the minimal erythema dose (MED) of NB-UVB is
;5 to 10 times that of BB-UVB.16 Maintenance
regimens varied and likely affected duration of
response.
Of the 58 patients who received home UVB
(emitted UVB of 280-350 nm), 48 of 58 had home
UVB alone and 10 had home UVB after office-
delivered phototherapy, which used a higher output
UVB lamp. A complete response was observed in 31
of 58 (53.4%) patients in those on home UVB alone
and 100% in those 10 patients on office/home UVB.
Maintenance was generally continued long term if
using home UVB, with only 2 of 18 patients having a
relapse while on phototherapy. Relapse was
common after maintenance phototherapy was
discontinued (12/23).12,14,23 Office-based BB-UVB
had an 89% CR in stage IA disease and a 44% CR in
stage IB disease, with 70% relapsing after discontin-
uing therapy.16 Patients treated with office-based
BB-UVB were much less likely to continue long-term
maintenance than home BB-UVB users. BB-UVB,
both home- and office-based, has been demon-
strated to be safe but has fallen out of favor as
demonstrated by a recent survey of cutaneous
lymphoma experts,17 being largely supplanted by
NB-UVB.
Efficacy of narrowband UVB (level of evidence
II-2)
The published studies in which NB-UVB has been
used to treat MF include [300 patients with MF, the
majority of them with early-stage disease ([95%
stage IA or IB, the rest primarily IIA).10-13,16,18-29
Evaluating the efficacy of treatment in these patients
is difficult given the variable definitions of clearance.
In general, a CR to therapy was defined as [90% to
95% clearance, which is different than the 100%
clearance of International Society for Cutaneous
Lymphomas (ISCL)/Cutaneous Lymphoma Task
Force of the European Organisation for Research
and Treatment of Cancer (EORTC)/USCLC guide-
lines and has obvious effects on remission rates.31
Evaluating only those studies in which concomitant
systemic treatments were excluded (Table I), the
reported CR rates for NB-UVB ranged from 54% to
90% (average, 84%). The frequency of NB-UVB
treatments was most often 3 treatments per week
(12/16 studies) initially, and this regimen was
continued until clearance or plateau in response.
Patients included in these studies ranged from
Fitzpatrick skin types I to VI and patch/plaque
disease with variation in escalation in dosage of
light, which may account for the wide range in the
J AM ACAD DERMATOL
n 2015
time and dose of UVB needed to obtain near
clearance. Patients with patch-only disease did better
with NB-UVB than those with plaques.14,15,26
Gokdemir et al26 did find that while the mean total
number of UVB sessions was not statistically
significant for patch vs. plaque disease, there was a
statistically significant difference (P = .04) in CR rates
for patch MF (100% CR) vs. plaque MF (60% CR).26 In
addition, Pavlotsky et al16 showed equivalency of
NBUVB (n = 68) vs. BBUVB (n = 43) in patch stage
IA disease (CR 84% vs. 89%, respectively) vs.
superiority in patch stage IB disease (78% vs. 44%,
respectively).16
Not unexpectedly, patients with a lower Fitzpatrick
skin type (I-III) did better than those with higher (IV-
VI) skin type; however, this was not a consistent
observation.24 Clinical clearing did not necessarily
correlate with histologic clearing.11,19,24,26 Of special
note, responders to NB-UVB included patients
previously treated unsuccessfully with PUVA.24,25
The definition of relapse, and therefore response
or relapse-free duration, also varied between studies.
Most frequently, relapse was defined as clinically
significant disease requiring further therapy vs. the
strict definition recommended for clinical trials of
MF.31 The relapse or recurrence rate after NB-UVB
was also dependent on the duration of follow-up in
each study and any maintenance treatment (defined
here as at least several months of reduced frequency
of phototherapy \2 times a week). Only 2 studies
had any maintenance treatment. For patients without
maintenance phototherapy, the relapse rate ranged
from 29% to 100%, with a mean relapse-free interval
(RFI) ranging from 5.9 to 14.5 months.10,18,21 Patients
with some form of maintenance therapy (including
both tapering over months and extended therapy
over years) had relapse rates ranging from 4% to
83%, with mean RFIs ranging from 3 to
26 months.19,24 Patients undergoing NB-UVB
therapy who continued on maintenance for a mean
of 3 months had a relapse rate of 35% after an
average follow-up of 77 weeks.16 Boztepe et al19
were able to show that of 8 patients with a CR who
had an extended maintenance protocol of a median
duration of 18 months, none relapsed and 6 of 8 had
a mean relapse-free duration of 26 months.19 The
remaining 2 subjects had a relapse at 20 and
21 months after CR. The authors concluded that
there may be a benefit to prolonged maintenance
protocol.
A previous survey and literature review demon-
strated that maintenance therapy regimens are
variable, ranging from no maintenance therapy to
use of maintenance therapy for $5 years.17 While
there are longer RFIs reported with the use of
 VOLUME jj, NUMBER j
J AM ACAD DERMATOL
Table I. Narrowband ultraviolet B light monotherapy for early-stage mycosis fungoides: Review of the literature
Type
Author(s), No. of Definition of Exposures to Definition of relapse/ of
year patients MF stage Regimen including mtn CR (% clear) No CR (%) CR/UVB dose relapse off therapy Observation period/RTI study

Ahmad 11 IA = 6; IB = 4; 33/wk until clear; 100 6/11 (55) ;19/median Clin sig dx/6 of 6 84 mo (range, 12-120)/ RSCS
et al, IIA = 1 no mtn ;20 J/cm2 median 11 mo
200718
Boztepe 14 IA = 4; IB = 6; 33/wk until clear, then $95 11/14 (79) 25.4 6 9.0/NS Clin and hist Median 22 mo (range, RCS
et al, IIA = 4 23/wk 3 3-6 mo, including 1 recurrence/1 on 17-43 mo) post-CR/
200519 13/wk 3 3-6 mo, on no mtn no mtn relapsed mean 26 mo (69.9)
qow 3 3-6 mo, at 6 mo; 2/8 who in 6/8 who
q mo 3 3-6 mo completed mtn completed mtn
(median duration relapsed at 10 and
mtn = 18 mo 21 mo, respectively
(12-30))
Brazzelli 20 IA = 10, 33/wk until clear, [95 18/20 (90) 29 6 14/25 6 Clin sig dx/100% NS/mean 8 mo PCS
et al, IB = 10 23/wk 3 4 wk, 16.77 J/cm2 (range, 3-17 mo)
200720 13/wk 3 4 wk
Clark 8 IA = 4, IB = 4 33/wk until clear; [90 5/8 (63) Mean 20/mean Clin sig dx/2 of 5 \3-40 mo/mean CS
et al, no mtn cumulative CR relapse off rx 20 mo: 3/5 remain
200011 25 6 17 J/cm2 in 1 and 40 mo, in CR, period
respectively unknown
Dereure 22 IA = 16; IB = 3; 33/wk until clear; [95 18/22 (82) NS for CR/NS Clin suspicion 26 mo (range, PCS
et al, IIA = 3 no mtn (assessment for CR confirmed 6-64 mo)/12
200921 2 mos with hist or clone/7 remain in CR
post-CR) of 18 (39%) relapsed
over mean 21 mo FU
(range, 4-48 mo)
Diederen 21 IA and IB 23/wk for 3-66 mo 100 17/21 (81) NS/NS NS/NS Mean FU 77 mo/ RSCS
et al, (mean 14 mo)dno mean 24.5 mo
200322 mention schedule (range, 2-66 mo)
post clearing
Gathers 24 IA = 12, 33/wk until clear, $95 13/24 (54); 52.2/mean Clin sig dx/no pts FU 32 6 11.2 wks RCS
et al, IB = 12 23/wk 3 4-8 wk, 8/12 IA and cumulative relapsed on mtn: 4/4 with 9 in CR on
200224 (all patch) q wk 3 4-8 wks 5/12 IB 94 J/cm2 (range, off mtn relapse mtn/NS
20.3-197.3 J/cm2) relapsed at a mean
of 3 mo (range,
1.5-6 mo)
Ghodsi 16 IA = 6, IB = 10 33/wk to clear; no mtn [95 12/16 (75) 27.9 (13-48)/ Clin sig dx/6 of 12 25 mo/4.5 mo (range, PCS

Olsen et al 5
et al, 26 J/cm2 relapsed in 25 mo FU 3-12 mo)
200525 (range, 48-65.4
J/cm2)
Continued
Table I. Contd

6 Olsen et al
Type
Author(s), No. of Definition of Exposures to Definition of relapse/ of
year patients MF stage Regimen including mtn CR (% clear) No CR (%) CR/UVB dose relapse off therapy Observation period/RTI study

Gokdemir 23 IA = 6; IB = 15; 33/wk until clear, then [90 21/23 (91); For patch CR: NS/1 of 21 Mean 11 mo FU PCS
et al, IIA = 2 (18 23/wk 3 4wk, patch 100%, 35/90 J/cm2; relapsed at 7 mo (range, 1-25 mo)/
200626 patch, 5 13/wk 3 4 wk, plaque 60% for plaque: NS 20 of 21 remain CR
plaque) longer if no
histological CR
Hofer 6 IA and IB 3-43/wk until clear, [95 5/6 (83) Mean 17.5 (range, NS/100% Mean 6 mo (range, PCS
et al, no mtn 15-29)/16 J/cm2 2-15 mo)/NS
199910
Kural et al, 23 IA = 10, IB = 13 33/wk until clear then [95 19/23 (83) Mean 26 (range, NS/7 of 19 within 8 mo NS/mean 16 mo Case
200627 mtn (no specifics) 12-64)/22.4 J/cm2 (unclear if on mtn) (range, 3-36 mo) series
(range, 5-68
J/cm2)
Ohtsuka, 8 IA = 4, IB = 4 13/wk initially 1 mtn [95 7/8 (88) NS/mean NS/no relapse on mtn; NS/22.5 6 18.5 wks Case
200828 q 2-4 wk for uncertain cumulative 1 on no mtn at 6 mo series
time period 8.2 J/cm2 post-CR
Pavlotsky 68 IA = 32, IB = 36 33/wk until clear, 100 53/68 (78) 12.8 wks/29 J/cm2 NS/35% relapse Mean FU 27 wk/65% RSCS
et al, 23/wk 3 4 wk, (8.2 6 3.4) (\3 mo relapse-free) remain in CR
200616 13/wk 3 4 wk then off rx within mean
q 2 wk 3 41 wks 27 wk
until sunlight biw
(Median 14 wk mtn)
Xiao et al, 8 IA = 2; IB = 3; 23/wk; mtn used $95 6/8 (75) Mean 23.4 6 8.5/ Clin sig dx requiring FU 7-60, mean 26.9 RCS
200812 IIA = 3 in 2/6 CR mean 12.6 6 more therapy/4 (69.7)/mean
(Fitzpatrick 4.7 J/cm2 of 6 within 8 mo 5 6 2.2 mo (range,
skin types (range, 3-6 mo) 3-8 mo) to relapse
III/IV)
Jang et al, 14 IA = 3, IB = 11 33/wk to clear; no mtn NS 11/14 (79) 31 6 7/4/ NS/6 of 11 (54%) mean 16.5 6 7.2 mo/8.5 mo PCS
200129 (Fitzpatrick noted 31.3 6 12.2 J/cm2 of 8.5 mo (range, 5-25 mo)
skin types
III-V)

Clin, Clinically; CS, case series; dx, disease; FU, follow-up; hist, histologic; MF, mycosis fungoides; mtn, maintenance; NS, not specified; PCS, prospective case series; pts, patients; RCS, retrospective case
series; RFI, relapse-free interval; RSCS, retrospective cohort study; sig, significant.

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VOLUME jj, NUMBER j
maintenance therapy, this comes at the expense of
additional cost of therapy, patient time, and
potentially additional side effects from UVB expo-
sure. What is needed to make data-driven decisions
regarding (1) the utility and (2) the schedule of
maintenance NB-UVB in MF is to first have the
definition of clearance meet ISCL/EORTC/USCLC
standards (ie, total clearance of visible disease).
The difference in the relapse rates of those treated
with maintenance NB-UVB vs. those without could
obviously be partially explained by the aggressive-
ness and thoroughness of clearance of lesions during
the initial therapy. Until additional research is
completed, we rely on available data and expert
opinion to help in making best decisions for thera-
peutic guidelines of NB-UVB in patients with MF.
Efficacy of combination therapy with UVB
(level of evidence III)
There are minimal data on the use of NB-UVB in
combination with other treatment modalities. One
case report demonstrated improved effect of NB-
UVB when combined with bexarotene 300 mg/day,
and another in conjunction with 75 mg/day of
bexarotene.32,33 A bilateral comparison study of
PUVA, psoralen plus NB-UVB, and NB-UVB
concluded that the addition of psoralen to NB-UVB
did not improve efficacy.23 One of our authors
standardly uses NB-UVB in conjunction with either
acitretin if the patient has a history of nonmelanoma
skin cancer (NMSC) or bexarotene if the patient does
not have a history of NMSC in all patients with either
stage IIA disease or those patients with IA or IB
disease who failed to respond to monotherapy with
NB-UVB (personal communication, Tom Anderson).
Efficacy of excimer laser (level of evidence
II-2)
Efficacy of the excimer laser in localized and
palmoplantar MF has been reported; a lower mean
cumulative dose for clearing was noted compared to
NB-UVB.6,34-38 It is difficult, however, to determine
best practices because there are so many treatment
variables with excimer laser including: (1) a starting
dose from 50 mJ/cm2 (as noted by Nistico et al6 and
Mori et al35) to \1 MED,34 to MED,38 (2) an interval
between treatments (7-10 days,6 23/week separated
by 2 to 5 days,34,38 33/week,36 as well as weekly,35)
and (3) incremental increases of dose.
SAFETY OF UVB PHOTOTHERAPY
Acute and subacute adverse events
The most common acute (within 24 hours) side
effects are erythema (;20%), pruritus (10%),
burning, tenderness, stinging, blistering, tanning,
Olsen et al 7
and xerosis.10-13,18,21-26,28,39 Erythema related to
NB-UVB has its onset at 2 to 6 hours after radiation,
peaks at 12 to 24 hours, and resolves largely in
48 hours.39 Overall, these side effects are not
treatment-limiting.
Exacerbation of preexisting dermatoses. These
include exacerbation of herpes simplex and
acne.13,25,40
Photosensitivity reactions to medications. The
action spectrum of the vast majority of photosensitizing
medications is in the UVA range. However, the
possibility of medications, especially newly developed
ones, in inducing NB-UVB phototoxicity needs to be
kept in mind. It should be noted that the administration
of topical or systemic retinoids may result in increased
sensitivity to NB-UVB. Treatment with NB-UVB can
uncommonly induce the development of lesions of
polymorphous light eruption. Although uncommon,
some photoactive medications, such as nonsteroidal
antiinflammatory drugs, calcium channel blockers, and
phenothiazines, may lower the narrowband MED.40
Idiopathic guttate hypomelanosiselike
lesions. This has been recently reported in 7 of 87
patients with MF treated with UV-based therapy (4
patients treated with NB-UVB and 3 patients treated
with PUVA). Treatment was discontinued in 4 of the 7
patients and the lesions had partial or complete
resolution in 3 of the 4 patients.41
NB-UVB induced lentigines. Although less
frequent than PUVA lentigines, NB-UVB induced
lentigines have been noted to occur with NB-UVB
therapy.42 Clinically, these appear as hyperpigment-
ed macules, less darkly pigmented and more
rounded and well circumscribed than that seen in
PUVA lentigos. They do not necessarily occur in
those with high total exposure to UVB, appearing
after a mean of 56 treatments in this one publica-
tion.42 Histologically, these are characterized by
basal hyperpigmentation without solar elastosis or
atypical melanocytes.
Effect on serum levels of vitamins
A. Folate. Photodegradation of folic acid by UVL is well
documented. However, whether NB-UVB affects
the serum levels of folic acid is controversial.43
B. Vitamin D. The action spectrum of vitamin D3
synthesis is in the UVB range (290-315 nm,
peaking at about 300 nm).44,45 Studies in both
psoriasis and controls have shown an increase in
serum levels of vitamin D metabolites in those
treated with either BB-UVB or NB-UVB.45
Chronic
Photocarcinogenicity. There is a concern of
increased carcinogenicity of NB-UVB over BB-UVB,
8 Olsen et al J AM ACAD DERMATOL
n 2015

stemming in part from mouse data showing that can be recommended for use in patients with eyelid
chronic exposure to NB-UVB induces more MF/SS.54
malignant tumors than BB-UVB.46 In addition, a Special populations. There is no restriction on
study on p53 mutations in patients with MF noted the use of NB-UVB in pregnant or pediatric patients
that there was an increase in mutations in with MF, as long as the latter can follow instructions
tumor-stage MF having a UVB signature as compared for phototherapy.
to plaque MF, leading to the hypothesis that UVB
damage may play a role in the progression from
PUVA THERAPY IN MF: CLINICAL
plaque to tumor stage MF in some patients.47
OUTCOMES
However, in a literature review published in 2005
Sources and dosing of psoralen
that included 11 studies of approximately 3400
In the United States, the only currently available
patients (primarily psoriasis) treated with BB-UVB
oral psoralen is 8-methoxypsoralen (MOP), which
or NB-UVB, there was no increase in skin cancer risk
comes in 2 commercial products, including an oral
with the exception of patients treated with both UVB
optimized methoxypsoralen called Oxsoralen-Ultra
and PUVA.48 A study of 3867 patients with psoriasis
(Valeant Pharmaceuticals, Bridgewater, NJ).55 The
from Scotland treated with NB-UVB supported this
psoralen binds to albumin, with 95% excreted as
finding, as the investigators found no significant
metabolites in the urine within 24 hours. Oxsoralen-
association between NB-UVB and skin cancer when
Ultra has a peak blood level at 0.5 to 4 hours (mean,
compared to age- and sex-matched controls. Their
1.8 hours) and peak photosensitivity at 1.5 to 2.1 hours
cohort of patients received a median of 29 treatments
and should be taken 1 to 1.5 hours before UVA
of NB-UVB (including 352 patients with [100
exposure. A previous nonoptimized 8-MOP oral
treatments) with a median follow-up period
preparation, no longer on the market, had a slower
of 5.5 years after the first 6 months of UVB.
peak absorption and therefore a different peak
Twenty-four percent of these patients had also
photosensitivity than Oxsoralen-Ultra. There are
received PUVA previously; in patients with a history
now generic oxsoralen ultra preparations that
of NB-UVB and PUVA, the authors did notice an
hopefully are not significantly different in these
increase in basal cell carcinoma alone.49 Both the
characteristics than the brand name product.
literature review and the retrospective study are
8-MOP is also available as a 1% topical solution
reassuring regarding the photocarcinogenicity risks
used for topical PUVA therapy and a sterile 8-MOP
of NB-UVB.
solution is available for use in extracorporeal
Ocular effects. A recent review on adverse
photopheresis (ECP). It should be noted that another
effects of UVL found convincing evidence that there
form of psoralen, 5-MOP, is less phototoxic and has
is a relationship between chronic UVL exposure and
fewer side effectsdparticularly less nauseadthan
cataract and pterygium formation.50 In 1 study, a
8-MOP. However, although 5-MOP is available in
high lifetime cumulative exposure to UVB
Europe, it is not available in the United States.
specifically was found to increase nuclear opacities
Trioxsalen, a synthetic psoralen, is another less
in women, and another study found an association in
phototoxic psoralen compared to 8-MOP; it is no
men between estimated total exposure to UVB and
longer available in the United States, but is available
the development of cortical opacities.51,52 Given the
in other parts of the world and is frequently used in
risk of ocular side effects from UVB, the use of eye
bath PUVA.
protection during UVB phototherapy treatments is
recommended to prevent excess UVB exposure and
thereby diminish the likelihood of subsequent Methods
naturally occurring cataract formation. It should be An extensive literature review was performed
noted, however, that there is only negligible using a PubMed search and was limited to original
transmission of UVL through the eyelids53; therefore, articles in which PUVA for MF or CTCL appeared in
for those requiring periocular treatment with the title and that was written in English or had an
NB-UVB, it can be achieved safely by keeping the English-language abstract. Review of the literature of
eyes closed. However, because patients may need to PUVA as monotherapy was performed separately for
open their eyes to maintain balance or for other early stage and advanced stage. Therefore, only
reasons while in the booth and in order to prevent reports in which analysis was provided separately
damage to ocular structures caused by the high for early and late stages of MF or the relevant data
intensity exposure, contact lenses have been tested could be retrieved from the results section were
to determine those which adequately protect against included. Levels of evidence are noted as was used
the NBUVB of phototherapy booths, and these for UVB above.
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
Efficacy in early stage MF (level of evidence II-1)
Background. PUVA as a treatment option for
MF was first reported by Gilchrest et al56 in 1976.
Since then, the efficacy of PUVA as monotherapy for
early-stage MF has been demonstrated in at least 20
studies.18,22,23,57-73 Publications were examined for
potential overlap of report of same cohort (for
example, Roenigk et al68 and Herrmann et al69),
and where noted, only the most recent report is
included in Table II. Reports including cases of early
MF treated concomitantly with (1) other skin tar-
geted therapies (except for cases treated with skin
targeted therapies clearly only for areas inaccessible
to UVL71) or (2) systemic therapies used in a signi-
ficant number of patients (eg, Ponte et al13) are noted
but excluded from the review of the literature of
PUVA as monotherapy in Table II. All reports except
for 363,67,71 were retrospective studies and, surpris-
ingly, despite the wide experience with PUVA during
the last 35 years, most of the studies included only
small series of patients. It is quite problematic to
summarize the results of the reports and to compare
between them, given that there were differences
in treatment protocols for the clearance phase,
dosimetry of 8-MOP without accurate weight
adjustment, and the use of 5-MOP in some reports
from Europe. In additiondand germane to the
reports of UVB and alternate forms of UVL used in
MF/SS as well as relevant to planning of clinical trials
that use phototherapydthe following problems
were identified:
Wide heterogeneity of the following:
A. Quality of studies
B. Sample size
C. Patient selection
1. Some series included patients who lacked a
definite diagnosis of MF and even showed
nonspecific histopathologic findings
2. Patients were either naive to previous specific
therapy or had been treated with previous
therapies and had now relapsed
3. Staging; some studies lacked TNM(B)
staging and only the type of lesion was
provided
D. Differences in outcome measures (ie, a lack of
information or consistency in the criteria used to
define CR), including the following:
1. Clinical definition alone
a. $80% clearing, [95% clearing; 100%
clearing; normal or quite normal look- difference between the 2 studies was caused only by
ing skin
b. Excluding the status of areas shielded
from UV in most reports
2. Clinical and histopathologic definition combined
Olsen et al 9
E. Lack of consistency in criteria defining relapse,
including the following:
1. Any new lesion
2. The return of clinically significant disease
F. Differences in definition of time of relapse,
including the following:
1. On or off phototherapy
2. Duration of response
3. Median or mean disease or RFI
4. Probability from relapse at 2 years and 5 years
G. Follow-up protocols and observation periods
Complete response rates after the initial
course of PUVA. Variable CR rates have been
reported for early-stage disease, ranging from almost
no case achieving complete clinical remission62 to a
100% CR rate.63 Based on a summary of the results of
the 6 studies in which tumor, node, metastasis
staging was provided,22,63,65,66,69,72 the CR rates
were calculated to be 85% for stage IA (130/152
patients), 65% for stage IB (114/175 patients), and
85% for stage IIA (30/35 patients). Based on the
experience of experts, patches and thin plaques are
known to respond better to PUVA than thick plaques;
however, the literature regarding the effect of
the type of lesion on the response to PUVA is
strikingly scarce. Briffa et al61 found that the CR
rate was 100% in their 25 patients with patch-stage
disease, while in their 28 patients with infiltrated
plaques it was 92%. Abel et al66 noted that the
thicker, more infiltrated plaques showed only partial
response.
Time to complete response. The largest series
with detailed information has been reported by
Hermann et al.69 Sixty-eight patients with early-
stage MF received PUVA 2 to 3 times weekly, of
whom 49 achieved clinical and histopathologic CR:
15 patients with stage IA after a median of 3 months
(range, 1-55 months), 29 with IB after a median of
2 months (range, 1-36 months), and 5 with IIA after a
median of 2 months (range, 1-6 months). No
specification as to the type of lesion was provided.
According to this study, the time to achieve CR in
early MF is a few months and does not seem to be
stage-dependent. Roenigk et al,68 also of
Northwestern University, reported that the time to
CR is much longer in patients with extensive plaque
MF compared with limited plaque MF (8 weeks and
30 weeks, respectively). It is unclear whether the
patient selection (3/27 patients with extensive pla-
que stage reported by Roenigk et al68 had advanced
stage with lymph node involvement). Whatever the
reason, both studies indicate that there is a fraction of
 10 Olsen et al
Table II. Psoralen plus ultraviolet A light monotherapy for early-stage mycosis fungoides: Review of the literature
No. of Phototherapy Exposures Relapse rate/ Remission
Author(s), pts/skin 8-MOP regimen, Definition No. of patients to CR/ definition Observation without Study
year type Stage/no. of pts dose including mtn of CR with CR, (%) time to CR of relapse period/RFI relapse type

Abel 13/NS IA/plq = 2; 0.65 2-33/wk, Clinical clearing IA, 2/2 (100); Data on 10 CR: 6/7 on mtn/ Mean FU after 1/7 RCS
et al, 1B/plq = 10; mg/kg tapering to IB, 5/10 mean 35 6 recurrent MF CR 50.3 (4.2)
198766 IIA/plq = 3 q mo mtn (50); IIA, 15/mean mo/data on 7
2/3 (66) 5.7 6 4.2 mo CR = mean
10.7 mo l
Ahmad 24/NS IA = 7; IB = 14; 0.6 2-33/wk; no mtn Clinical IA, 7/7 (100); NS 100%/clin Median FU 72 mo NR RC
et al, IIA = 3 mg/kg disappearance IB, 6/14 (43); significant (range, 12-310)/
200718 of all lesions IIA, 3/3 (100) disease median RFI:
IA, 16.8 mo; IB,
15.7 mo; IIA,
14.3 mo
Bleehen 24/NS NS/infiltr plq = 7; 0.6 2-33/wk then q 100% clinical Infilt plq, 7/7
NS/NS/in most NS/NS [1 year/NS NS RCS
et al, NS/plq = 17 mg/kg wk-q mo clearing (100); plq, stage I within
197858 long term 14/17 (80) 10 wks, stage
II longer
Briffa 53/NS NS/patch = 25; 0.6 2-33/wk, mtn in Clear clin Patch, 25/25 Patch, mean 7/13 patch and Mean 19 mo Patch 12/25, RCS
et al, NS/plq = 28 mg/kg most as and hist (100); plq, 19 6 8 wks; 21/26 plq/NS (range, 2-39) plaque
198061 infrequent 23/25 plq, 18 6 7/NS FU/relapse 7/23
as q mo; patch: without XRT time patch: 7/13
1 no mtn, 13 (92) after DC mtn,
mtn 3 mean 0/6 on mtn;
12 mo, 11 cont relapse plq:
mtn; plq: 4 no 3/4 @ 7 mo
mtn, 4 mtn after DC mtn,
mean 16 mo, 15/18 on mtn @
18 cont mtn, mean 13 mo,
2/18 with XRT and 1/4 on no
mtn @ mean
5 mo
Diederen 35/NS IA-IIA = 35 NS 23/wk; mtn NS No disease 25/35 (71) NS NS/NS Mean FU 45 mo/ NS RCS
et al, but mean activity mean 22.8 mo
200322 11 mo (2-37) (range, 1-43)
El-Mofty 20/III IA = 4 patch 0.7 33/wk 3 $80% clinical 14/20 (70) NR/NR NR/NS No FU/NR NR RC

J AM ACAD DERMATOL
et al, or IV and plq; mg/kg 12 or 16 improvement
200523 IB = 13 patch wk to half
or plq; of body
IIA = 3 plq only;
no mtn

n 2015
 VOLUME jj, NUMBER j
J AM ACAD DERMATOL
Gilchrest 2/N IB ext plq = 2 0.6 2-43/wk $95% clin clear 1/2 (50) 12/4.5 wks NS/NS NS NS RCS
et al, mg/kg decreased to
197656 once weekly;
mtn NS
Herrmann 74/NS IA = 19; IB = 49; 0.6 2-33/wk to Clin and hist IA, 15/19 (79); Median mo: IA, 3 IA, 5/15 (33%); Median FU Freedom RCS
et al, IIA = 6 mg/kg clear mtn clear 3 IB, 29/49 (range, 1-55); IB, IB, 11/29 42 mo from
199569 q wk 3 2-6 wk, $4 wk (59); IIA, 2 (range, 1-36); (40%); IIA, (range, relapse
qowk 3 8 wk, 5/6 (83) IIA, 2 (range 1-6) 1/5 (20%) 2-177)/NS at 2 and
q 3 wk 3 12 wk 5 y: 67%
then q 4 wk and 58%,
indefinitely 41% and
25%, and
67% and
67%,
respectively
Hodge 3/NS NS/infiltr plq = 3 30- 33/wk; mtn NS Resolution 3/3 (100) NS NS/NS NS NS R case
et al, 50 mg lesions series
197757 or healing
ulcerating
lesions
H
onigs- 35/NS IA = 9, IB = 26 NS 43/wk until Complete IA, 9/9 (100); IA, 50 d 6 41/ IA, 4/9 (44%); FU 6-84 mo/IA, IA, 7/9 clear, PCS
mann clear, then clearing IB, 26/26 mean 19 6 15; IB, 16/26 mean 20 6 21 mean 48
et al, in all: 23/ (100) IB, 44 d 6 38/ (62%); mo; IB, mean mo (range,
198463 wk 3 1 mo, mean 19 6 14 definition 17 6 16 mo 6-71) after
13/wk 3 NS last Rx; IB,
2 mo. In 23%, 17/26 clear,
additional mean 31 mo
3-5 mo until (range, 3-73)
remission
Lowe 4/NS NS/infiltr plq = 4 0.6 QOD; mtn as Substantia 4/4 (100) Mean, 17 (range, 2/4 off therapy/ 0.5-2.25 years NS RCS
et al, mg/kg infrequent improvement 12-22)/NS any new lesion after starting
197960 as possible PUVA/2.5 wks
to control in 2 CRs off Rx
disease
Oguz 58/NS IA = 44; IB = 7; NS 43/wk until clin Clin and hist IA, 44/44 (100); NS/NS NS/IA, 4-y FU after 69% patch RCS
et al, IIA = 6 and hist CR clear IB, 7/8 (87); 39 6 2 mo; completion and 69%
200370 then q 4-6 IIA, 6/6 (100) IB, 34 6 8 mo; of PUVA/ plaque
wk 3 6 mo IIA, 22 6 5 mo mean 37 mo CR at mean
duration
FU 32 mo

Olsen et al 11
Powell 10/NS NS/patch = 6; 30- 33/wk until Clin clear Patch, 4/6 (66); Patch, Minor relapse/ Patch: FU mean 17 NS RCS
et al, NS/plq = 4 50 mg substantial plq, 3/4 (75) NS/24-151 patch, 1/4; (range, 3-44)
198464 clearing, then (mean, 49); plq, 2/3 mo/NS; FU
reduced freq plq, NS/16-128 plq 15 (range,
until clear (mean, 55) 3-39) mo/NS
clin and hist;
no mtn
Continued
Table II. Contd

12 Olsen et al
No. of Phototherapy Exposures Relapse rate/ Remission
Author(s), pts/skin 8-MOP regimen, Definition No. of patients to CR/ definition Observation without Study
year type Stage/no. of pts dose including mtn of CR with CR, (%) time to CR of relapse period/RFI relapse type

Querfeld 104 IA = 57; IB = 42; NS 2-33/wk until Clin and hist IA, 39/57 (70); NS/median 3 mo 33/66 (50%)/clin Median FU 94 30% of IA RCS
et al, IIA = 5 CR then clear 3 IB, 22/42 significant mo all patients and 50%
200571 tapered to $4 wk (52); IIA, 5/5 disease 49/66 FU min of IB/IIA
q 1-6 wk mtn (100) requiring more 60 mo, 17/66 remain in
indefinitely intensive PUVA FU median continuous
or other Rx FU 29 mo/3/5 remission
off PUVA relapsed ;10 y
mean 64 mo and after
2/5 w/o PUVA still initial
CR at 24 and treatment
86 mo
Rabbiosi 34/NS IA = 6; IB = 13; 0.6 43/wk, mtn BIW Clin and hist IA, 6/6 (100); NS/mean IA, 2/6 (33%); FU 1-5 y/NS NS RCS
et al, IIA = 15 mg/kg or q wk 3 2 mo clear IB, 11/13 IA, 6 6 5 wks; IB, IB, 11/13
198665 (84); IIA, 8 6 4 wks; IIA, (84%); IIA,
12/15 (80) 9 6 8 wks 12/12 (100%)
@ 6 or 12
wks
Roenigk, 7/NS NS/plq = 7 20- 33/wk, mtn 100% clin clear 7/7 (100) NS/NS NS/NS Average FU ea NS RCS
197759 50 mg 1-23/wk-qowk CR $ 1 y/NS
indefinitely
Rotstein 8/NS NS/patch = 6; 0.6 23/wk; mtn Clin clear NS, 1 used Mean 30 of 6 pts NS/100% 0-8 mo off NR RCS
et al, NS/plq = 2 mg/kg frequency NS XRT lesion known to reach therapy/NR
198062 on thigh CR/NS
Thomsen 47/NS NS/plq 0.6-0.8 23/wk or 43/ Clin and hist 34/47 (72) 2 3/wk mean NR NR NR PC
et al, stage = 47 mg/kg wk till clear 42 to CR/NS;
198967 2 wk post CR, 43/wk mean
no mtn 20 to CR/NS
Wacker- 24/all IA = 11; IB = 12; 0.6 mg/kg 2-43/wk until clear, Clin clear 22/24 (92) Mean 32 17/22 (77%)/ FU mean 13 NS RC
nagel types IIB = 1 5/24 (range, disease (range, 4-33)
et al, I-III pts with CR 14-79)/mean recurrence mo/14 mo
200672 had mtn 1-23/ 101 d (range, (range, 4-33)
wk 3 15 Tx 53-409)
Wacker- 14/all IA = 6, IB = 8 5-MOP 2-43/wk until clear, Clin clear 12/14 (86) Mean 25 (range, 11/12 (92%)/ FU mean 16 NS RC
nagel types 1.2 4/14 pts with 8-60)/mean 79 d disease (range, 4-31)

J AM ACAD DERMATOL
et al, I-III mg/kg CR had mtn (range, 22-171) recurrence mo/17 mo
200672 1-23/wk 3 15 Tx (range, 4-31)

BIW, Twice weekly; clin, clinically; CR, complete response; DC, discontinue; RFI, relapse-free interval; Ext, extensive; FU, follow-up; hist, histologic; improve, improvement; infiltr, infiltration; min,
minimum; mtn, maintenance; NR, not relevant; NS, not specified; plq, plaque; q, every; qo, every other; QOD, every other day; PC, prospective comparative; R, remission; RC, retrospective
comparative; RCS, retrospective case series; Rx, treatment; w/o, without; XRT, radiation therapy.

n 2015
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
patients with early MF that needs long periods of
PUVA to achieve CR.
The effect of the type of lesion on the time to CR
has been evaluated in few studies. Briffa et al61 found
that patients with infiltrated plaques needed double
the time to achieve CR compared to patients with
patches. Likewise, Bleehen et al58 noted that several
of their MF patients with infiltrated plaques cleared
more slowly than patches, and Rabbios et al65
reported that plaques with minimal infiltration
cleared more rapidly than infiltrated plaques.
Effect of type of psoralen and clearing phase
protocol on the response
A. Psoralen. In general, the psoralen most often
used in the studies reviewed was 8-MOP. 5-MOP
has been used as an alternative to 8-MOP in
treating diseases other than MF, primarily in
Europe, exhibiting equal efficacy and better
tolerance. In a retrospective comparative study
reported by Wackernagel et al,72 5-MOP and
8-MOP were found to have comparable thera-
peutic efficacy in early-stage MF.
B. PUVA sessions are given 2 to 4 times weekly.
Whether the frequency of PUVA sessions affects
the response in MF has hardly been investigated.
Thomsen et al67 noted that patients receiving
PUVA twice a week needed more sessions to
achieve CR compared to those treated 4 times
weekly. Likewise, the dosage of UVA at
remission was significantly lower if treatment
was given 4 times instead of 2 times weekly.
Effect of skin phototype on response to
PUVA. In psoriasis, it has been found that patients
with Fitzpatrick skin types V and VI are less respon-
sive to PUVA or NB-UVB than those with skin types I
through IV.74 In contrast, there are no published data
comparing the effect of skin phototype on the
response to PUVA in patients with MF; in fact, the
skin types of patients are not mentioned in most of
the published reports. Honigsmann et al63 reported
that some patients who developed pronounced
pigmentation during PUVA treatment required an
extremely high number of exposures for clearing. El
Mofty et al75 found that clearance of early MF lesions
in their series of patients treated by either PUVA or
NB-UVB occurred in double the number of sessions
needed to treat patients in a previous study of
NB-UVB and early MF. They postulated that the
darker skin types in their patients (ie, Fitzpatrick skin
types III, IV, and V) may have accounted for this
difference.
Follow-up data after an initial course of
PUVA without maintenance. Data on the
disease-free intervals and the relapse rates in patients
Olsen et al 13
achieving CR after an initial course of PUVA without
long-term maintenance protocol are sparse,18,63,65
with results that are somewhat conflicting. Ahmad
et al18 reported that all 24 MF patients with stages IA
to IIA who achieved CR without receiving any
subsequent maintenance therapy relapsed after a
median period of 15 months. No difference was
found between those with different stages. On the
other hand, Honigsmann et al63 reported that
although the majority (58%) of their 35 patients
with IA or IB disease who achieved a CR following
43 weekly treatment relapsed during the observa-
tion period, the remaining 42% had a sustained
remission (mean duration of 4 years [range,
6-71 months] in those with stage IA disease [5/9]
and 2.5 years [range, 3-77 months] in those with stage
IB disease [10/26]). Of note, in the latter study, a short
period of maintenance therapy of 2 months was
given after the clearing phase. According to this
study, in some patients with early MF, a CR of up to
6 years may be sustained without the need for a long-
term maintenance therapy. Although the observation
period does not prove that PUVA can induce a
permanent cure, it nevertheless demonstrates that
long-lasting disease-free intervals are possible after 1
course of PUVA in early-stage MF.76 In agreement
with the experience of Honigsmann et al,63
Vonderheid77 in a review article stated that in some
patients with early (IA) stage MF, a CR may be
sustained without maintenance treatment.
Effect of stage and type of lesion on relapse
rate. Published data regarding the effect of the
stage and the type of lesion on the relapse rate in
PUVA treated patients are strikingly limited.
According to the experience with a limited number
of MF patients with stage IA and IB published by
Honigsmann et al,63 it seems that the incidence of
relapse parallels the stage of the disease. Ahmad
et al,18 who did not use maintenance, reported that
the median disease-free interval for patch stage was
12.1 months compared to 10.2 months for plaque
stage. In both studies, however, the number in each
group was too small to reach a definite conclusion.
Follow-up data after initial course of PUVA
with maintenance. In the majority of the studies,
patients continued with maintenance treatment for
variable time periods after achieving CR in order to
prolong remission. Although some textbooks and
review articles state that maintenance does prolong
remission, the results of the literature are not
clear-cut because of the heterogeneity in the
methodologies used in the reports. Clearing was
often not defined as 100% clearing, which then
confused the meaning of RFI that was measured in
follow-up. There were also differences in the interval
14 Olsen et al
between treatments (not only between the different
studies but also between different patients in the
same study) and the duration of therapy after
clearing (ranging from several months to indefi-
nitely). In 1990, Roenigk et al68 reported on a group
of MF patients treated with PUVA at Northwestern
University, Chicago. After the clearing phase, most of
the patients received continuous maintenance
treatment once weekly for 2 weeks, followed by
once every 2 weeks for 8 weeks and then once every
4 weeks, but the exact numbers in each group were
not provided. Of the 15 patients with limited
plaque-stage MF (IA in terms of tumor, node,
metastasis classification) who achieved CR, 53%
experienced relapse (definition was not provided)
after a mean period of only 8 weeks. The remaining 7
patients had no relapse at all during the mean
observation period of 41 months (range,
0.5-10 years), including 4 of these off PUVA up to
62 months. Fifteen years later, Querfeld et al71
reported the long-term outcome of 66 patients with
early-stage MF (IA-IIA) who achieved a CR and were
treated at Northwestern University: it is unclear to
what degree there was overlap with those reported
earlier by Roenigk et al,68 but it is the consensus of
the authors of the papers in question that they
represented primarily separate populations. The
vast majority of the patients were on continuous
maintenance therapy, the number of treatments
gradually reduced to 1 every week to 6 weeks at a
constant dose. Overall, in this retrospective study,
although 50% of the patients experienced relapse
(defined as return of clinically significant disease
requiring resumption of more intensive PUVA), the
time to relapse was long with median disease-free
interval of 39 months (range, 2-127 months). This
disease-free interval seems much longer than
observed by Honigsmann et al63 in patients who
were prospectively followed up after completion of a
short period of maintenance therapy (definition of
relapse was not specified). The other 50% of the
patients reported by Querfeld et al71 had a sustained
remission of a median duration of 84 months (7 years;
range, 5-238 months [ie, 0.5-20 years]). Ninety-four
percent received maintenance therapy at the time of
this assessment. Therefore, long-term maintenance
treatment is associated with long-term remission.
Half of the patients with early MF reported by
Honigsmann et al63 also had sustained remissions
despite the lack of long-term maintenance after CR.
However, the mean duration of remission was
shorter than reported by Querfeld et al.71 The
possibility that the different outcomes between these
2 studies can be attributed to different definitions
of relapse and to the overall shorter observation
J AM ACAD DERMATOL
n 2015
period in Honigsmann et als study63 cannot be
ruled out.
Follow-up data after initial course of PUVA
with and without maintenance. There is only 1
study, albeit a small number of patients, that
compared the follow-up data between a group of
patients with and without maintenance treatment
after the initial clearing phase of PUVA. In this
retrospective study of patients with stage IA
(n = 17), IB (n = 20), and IIB (n = 1) lesions treated
with either 8-MOP or 5-MOP and UVA 2 to 4 times per
week until clinical disappearance of all lesions,
Wackernagel et al72 did not find any significant
difference in the relapse rate or in the time to relapse
between the group of 25 early MF patients who
stopped PUVA after the clearing phase and the group
of 9 patients who received maintenance treatment 1
to 2 times weekly at a constant dose for a target of
another 15 treatments (range, 0.3-10.5 months). The
results of this study suggest that relatively short-term
PUVA maintenance treatment may not necessarily
slow disease recurrence.
Points not addressed by the available
studies. There are 2 additional points not
addressed by the available studies: (1) the impact
of the maintenance protocol on the outcome,
including the different intervals of treatments, and
(2) the relapse rates once long-term maintenance is
stopped.
Summary. The available studies are mostly
retrospective and uncontrolled, and there is an
unmet need for a randomized, controlled study in
order to clarify the multiple variables surrounding
the issue of maintenance therapy with PUVA that
may affect efficacy. The importance of solving this
controversy is further emphasized by the following
observations:
A. It seems that most of the patients who respond
to the first clearing phase of PUVA therapy will
respond to the second clearing phase, as
reported by Abel et al66 and Querfeld et al.71
In addition, Wackernagel et al72 did not find any
significant differences between the first and the
second course of PUVA in terms of treatment
duration, treatment number, or cumulative dose
until CR or in terms of relapse, although the
number of the studied patients was limited.
However, retreatment is expensive in both time
and cost because patients must begin again at 2
to 3 times per week.
B. Sustained remissions under PUVA maintenance
therapy were not shown to affect long-term
survival by Querfeld et al,71 because the overall
survival rate for the nonrelapse and relapse
groups did not show any statistical difference.
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
During the follow-up period, of the 66 patients,
50% maintained a CR and 50% experienced
relapse. There was no statistical difference in
overall survival between the nonrelapse and
relapse cohorts. Therefore, long-term survival is
not necessarily affected by relapse status.
C. Because UVA is more penetrating than UVB,
PUVA is more effective than UVB for thicker
lesions, or in individuals with dark skin.
D. Chronic treatment with PUVA is well known for
its carcinogenic effects; it is important to limit
unnecessary exposure.
Efficacy in advanced-stage MF (level of
evidence II-3)
See Table III.
Tumor stage. PUVA given as monotherapy
yields low rates of CR in patients with tumors;
among the 71 patients with tumor-stage MF pub-
lished in the literature, only 20 (28%) achieved a
CR.18,56-58,60,61,65,69,78 The time to achieve a CR in
tumor-stage MF was found to be longer compared to
early-stage MF in all the studies summarizing data of
both stages. In most of the studies, maintenance
therapy was given, but data on the exact duration of
maintenance are lacking. Relapses were commonly
seen, but the duration of a disease-free interval was
provided only in 2 studies by Briffa et al61 and
Herrmann et al69; the mean duration of remission
under continuous maintenance treatment was
19 months and 9 months, respectively.
Erythrodermic MF with or without SS. Overall,
37 patients with erythrodermic MF, with or without SS,
who received PUVA as monotherapy were published
in the literature with a CR rate of 43% (16/37
patients).18,56,59,60,62,63,66,68,69,79 There are a few
studies in which analysis was conducted separately
for SS and erythrodermic-stage MF. Abel et al66 found
that all the 7 patients with erythrodermic MF but
without SS achieved a CR after the clearing phase, and
thereafter achieved good control under continuous
maintenance treatment. After clearing, a tapering
maintenance schedule was begun once weekly for 2
to 6 weeks, every 2 weeks for 8 weeks, every 3 weeks
for 3 weeks, or once monthly depending on the
clinical course (despite minor recurrences) for a mean
of almost 5 years. In contrast, none of the 5 patients
with SS managed to go into remission. Patients with
erythroderma required a greater number of treat-
ments to clear (mean, 43.6 treatments) compared with
patients with plaque stage (mean, 35 treatments).
However, the mean UVA dose attained at clearing was
much lower in the group with erythroderma
compared with patients with plaques because they
could tolerate only small doses of UVA due to extreme
Olsen et al 15
photosensitivity. Herrmann et al69 also reported that 2
of 3 patients with erythroderma achieved CR as
opposed to none of their 3 patients with SS.
Although the erythroderma in 2 of the 3 SS patients
showed a partial response, no change in the S
ezary
cell count was detected. Likewise, no change in the
number of circulating S
ezary cells was observed in the
2 of the 7 patients with SS who achieved a CR as
reported by Roenigk et al.68 However, in other
reports, it has been noted that PUVA may affect the
blood tumor burden.40
SAFETY OF PUVA
Acute side effects
Psoralen-related. Nausea and abdominal pain
are the most common acute side effects of 8-MOP
intake, affecting up to 20% of patients. In contrast,
5-MOP intake is not associated with gastrointestinal
side effects.72
Hepatotoxicity is rare.
PUVA-related
A. Erythema. Common acute toxicities of PUVA
therapy include erythema (onset of 24 hours,
peaks at 48-96 hours, and resolves over the
week after treatment), blisters, pruritus, stinging
pain in circumscribed areas, and xerosis.
Phototoxic reaction/erythema is the most
common early cutaneous side effect of PUVA,
occurring in 10% to 20% of treated patients.
These can be managed by altering the dosage of
UVA, holding therapy when clinically indicated,
and the liberal use of emollients.
B. Fatigue and headache.
C. Photosensitivity. Photoallergic reaction is rare.
Precipitation of polymorphous light eruption can
occur but is uncommon. Patients with MF/SS
who are undergoing PUVA therapy may also
exhibit unusual photosensitivity for their skin
type; this is usually related to medications or
supplements that the patients are taking,
because the action spectrum of most drug-
induced phototoxicity is in the UVA range.
D. Unveiling of preexisting lesions. Uncommonly,
during the initial treatment, MF lesions may be
more pronounced in appearance.80 In addition,
in some patients, the first PUVA exposures result
in the emergence of new erythematous lesions
resembling MF lesions in previously normal-
appearing skin that were not detected clinically
before PUVA.63,80 This phenomenon appears to
be related to the unmasking of new lesions of
MF,80-82 which is similar to that seen with topical
nitrogen mustard.
E. Nail changes. These may include subungual hem-
orrhage, photoonycholysis, and melanonychia,39
Table III. Psoralen plus ultraviolet A light monotherapy for advanced-stage mycosis fungoides: Review of the literature

16 Olsen et al
Classification/ Exposures to CR/
Author no. of patients Definition of CR 8-MOP dose/frequency of UVA including mtn No. of CR time to CR Follow-up data

Abel et al, 198766 Erythroderma = 7; Clinical clearing 0.65 mg/kg/2-33/wk; mtn indefinitely T4: 7/7 (clinical Mean 43.6 6 24 mo/ Mean FU post CR = 70 mo
SS = 4 clearing); mean 5.2 6 3.8 mo (5.3 y); majority of pts
SS: 0/4 relapsed after mean
22.2 months; 1 T4 MF RTI
43 mo with mtn
Ahmad et al, Tumor = 2; Disappearance of 0.6 mg/kg/33/wk until clear; no mtn T3: 1/2; T4: 1/1 NS T3: 10 mo RFI; T4: 4 mo RFI
200718 erythroderma = 1 all lesions
Bleehen et al, Tumor = 12 100% clinical clearing 0.6 mg/kg/2-33/wk then qwk-q mo mtn 3/12 NS slow response Relapses during maintenance
197858 commonly seen
Briffa et al, 198061 Tumor = 18 Clear clinical and 0.6 mg/kg/2-33/ wk, mtn indefinitely 6/18 1 2 Mean 26 6 10/NS Obs mean 19 mo (range, 2-39);
histologic clearing additional with mean duration of remission
local XRT 19 mo (2 pts had minor
recurrences requiring
more freq Rx)
Gilchrest et al, Tumor = 2; $95% clearing ;0.6 mg/kg/2-43/wk decreased to once T3: 1/2; T4: 1/3 T3: 35/6 wks; T4: Both CR remained clear
197656 erythroderma = 3 weekly; mtn NS 76/28 wks for 28 mo
Herrmann et al, Tumor = 1; Clinical and histologic 0.6 mg/kg/2-33/wk to clear, then taper T3: 1/1; T4: 2/3; T3: NS/2 mo; T4: Tumor relapsed @ 9 mo;
199569 erythroderma = 3; clearing 3 $4 wks to q 12 wks over 22-26 wk, then SS: 0/3 NS/7 mo; SS: NR erythrodermadwith reRx,
SS = 3 indefinite mtn 1/2 remains in remission
at 2 y
Hodge et al, Tumor = 3 Resolution lesions 30-50 mg/kg/33/wk; mtn NS 1/3 NS NS
197757 or healing of
ulcerated lesions
H
onigsmann Tumor = 7; Complete clearing NS/43/wk till clear then BIW 3 1 mo, T3: 0/7; T4: 2/2 T3: NR; T4: 35 6 20/ T3 obs 51 6 14 mo; T4 obs
et al, 198463 erythroderma = 2 then q wk 3 1 mo 48 d 6 40 19 6 16 mo: 1/2 recurred
on mtn, 1/2 clear at 30 mo
K
ovary et al, SS = 4 Marked reduction in 0.6 mg/kg/4 3 /wk till clearing then 4/4 clinical Mean 14.5 (range, 2/4 retain excellent response at
198179 scaling, erythroderma, BIW 3 4 wk, then q wk resolution 11-20)/NS 18-20 wk FU; no effect on
and pruritus blood S
ezary cells
Lowe et al, SS = 1; tumor = 5 Substantial 0.6 mg/kg/QOD; mtn while continued SS: 0/1; T3: 1/5 SS: NR; T3: 30/NS FU 0.5-2.25 y after starting
197960 improvement to control disease as infrequent as PUVA; relapse of CR 13 wks
possible off PUVA
Molin et al, Tumor = 15 0.6-0.8 mg/kg/43/wk 1 mtn indefinitely 5/15 1-3 mo
198178 q wk-q mo
Rabbios Tumor = 5 Clinical and histologic 0.6 mg/kg/43/wk then q wk to 1/5 NS/NS One CR relapsed

J AM ACAD DERMATOL
et al, 198665 clearing qowk 3 2 mo
Roenigk, 197959 Erythroderma = 1; At 50 kg, 20 mg; 51-65 kg, 30 mg; T4: 1/1; SS: 2/5 NS
SS = 5 66-80 kg, 40 mg; 80 kg, 50 mg 33/wk;
mtn 1-23/wk-qowk indefinitely
Rotstein Tumor = 1; Clinically clear 0/6 mg/kg/23/wk; mtn NS T3: 0/1; T4: 0/1 NR/NR NS
et al, 198062 erythroderma

n 2015
with nodes = 1

BIW, Twice weekly; NS, not specified; NR, not relevant; q, every; qo, every other; SS, S
ezary syndrome; mtn, maintenance; pt, patient; PUVA, psoralen plus ultraviolet A light phototherapy;
XRT, radiation therapy.
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
all affecting multiple nails. The latter usually
occurs in patients with Fitzpatrick skin types IV
to VI. One can continue to treat despite the nail
changes, because these changes are
fully reversible once PUVA is discontinued. The
application of nail lacquer may prevent the
appearance of these nail changes (E. Hodak,
personal observation).
F. Pigmentary changes. These include:
1. Immediate pigment darkening and persistent
pigment darkening (caused by oxidation of
preexisting melanin)83
2. Significant delayed tanning response, especially
in those with Fitzpatrick skin types III to VI
3. Pigmented macules appearing in the clearing
phase restricted to resolving plaques of MF56,80
4. Mottled hypo- and hyperpigmentation, which
can occur as early as 4 weeks into therapy84
G. Vitiligo-like leukoderma.80,85
H. Uncommon side effects, including reactivation
of herpes simplex, exacerbation of systemic
lupus erythematosus or bullous pemphigoid,
and an acneiform eruption.86
Chronic
Pigmentary changes. The side effects of
long-term PUVA therapy have been investigated
extensively, especially in patients with psoriasis.
PUVA lentigines. The frequency of PUVA lenti-
gines and their severity are directly correlated with
the total number of treatments and have been
observed in [50% of patients treated with PUVA.87
PUVA lentigines have subtle differences from solar
lentigines: clinically, they commonly occur in
nonesunlight exposed areas, are often more darkly
and unevenly pigmented, and pathologically, there is
no solar elastosis and cytologic atypia is commonly
seen.88,89 The T1799 A BRAF mutation, commonly
found in patients with melanoma and pigmented nevi,
was detected in 33% of cases with PUVA-induced
lentigines in 1 study.90 However, so far no increased
risk of melanoma associated with these lentigines
has been recorded. The lentigines seen with NB-UVB
have different characteristics than PUVA lentigines.42
Idiopathic guttate hypomelanosiselike lesions. This
has been reported after a prolonged therapy (mean
number of 137 PUVA exposures) in areas exposed to
UVA, and not exclusively to skin previously involved
by the disease.41
Photoaging. With long-term PUVA therapy,
most patients develop wrinkling and telangiectasia
clinically91 and elastosis histologically.92
Olsen et al 17
Hypertrichosis. Hypertrichosis93 is a rare con-
dition with PUVA, reported primarily in patients
being treated for vitiligo.
Ocular changes. Psoralens are absorbed by the
lens94 but will diffuse within 24 hours without
exposure to UVA. In the presence of UVA, the
8-MOP binds to nucleic acids and proteins in the
lens and remains for long periods of time, theoret-
ically increasing the risk of cataractsdthis is the
rationale for wearing UVA-absorptive eye protection
during exposure to sunlight after psoralen ingestion.
A 25-year prospective study of patients treated with
PUVA from a large United States cohort study did not
demonstrate an increased risk of either visual
impairment or cataract formation with increasing
exposure to PUVA,95 most likely because of the
regular adherence to this recommendation for eye
protection.
Effect on serum vitamins. Folate. A decrease
in serum folate upon exposure to PUVA has been
reported in a trial of ECP and in a study of in vitro
exposure of plasma from healthy individuals.
However, reports of decreased serum folic acid from
PUVA are inconclusive.96
Skin cancer.
NMSC. High cumulative exposure to oral PUVA is
associated with a dose-related increase in the risk of
NMSC, particularly squamous cell carcinoma
(SCC).97-99 A metaanalysis of several PUVA trials
revealed a 14-fold increased incidence of SCC in
patients with psoriasis who received high-dose
PUVA ([200 treatments or [2000 J/cm2) compared
with those who received low-dose PUVA (\100
treatments or \1000 J/cm2).100 In a follow-up study
on patients with early stage MF under continuous
maintenance therapy of about every 6 weeks, 26%
developed NMSC, including SCC (in situ and
invasive) and basal cell carcinoma.71
In studies from the United States, the risk of SCC of
the male genitalia in psoriasis patients treated with
PUVA is particularly elevated,100-102 which is why it is
recommended that this area be shielded during
PUVA treatments unless there is a persistent area of
MF that is not responsive to alternative therapy.
Melanoma. Whether exposure to PUVA increases
the risk of developing melanoma is an area of
controversy. Numerous studies of patients with
psoriasis from Europe treated with PUVA have not
shown an increased risk for developing mela-
noma.103,104 However, a 15-year follow-up study of
PUVA-treated psoriasis patients in the United States
found that although there was no increased risk of
melanoma over the first 10 years of follow-up, there
was a higher risk of melanoma after a latency period
of at least 15 years and/or high level of exposure
18 Olsen et al
([250 PUVA treatments used as benchmark) with a
relative risk of 3.1 if both were present.105 Follow-up
of these patients for an additional 27 months showed
an incidence of invasive melanoma 10 times higher
than that of the general population, although an
acknowledgement was made by the authors that
other potential risk factors were unaccounted for.106
It should be noted that not enough nonwhite
patients were present to assess risk in this group.
Of note, there are other US studies that do not show
an increased risk of melanoma in psoriasis patients
treated with PUVA.105,107 The risk of melanoma has
been noted in 1 study to be greater in patients with
CTCL.108
Other cancers. Lunder and Stern109 reported that
the incidence of Merkel cell carcinoma was about
100 times higher among patients with psoriasis
treated with PUVA than that expected in the general
population. There is no similar report in MF/SS
patients. The results of this study need to be
confirmed by others.
COMBINATION THERAPY WITH PUVA IN
MF
Background
To improve efficacy and possibly prolong remis-
sion in patients with early-stage MF with insufficient
response to PUVA alone or in patients in whom
lower response rates with PUVA alone are expected
(such as in cases with thick plaques or folliculotropic
MF), combination treatments are used. A combina-
tion of PUVA with systemic therapy may also
decrease the total UVA exposure and therefore
reduce the long-term side effects. Patients with
more advanced MF may benefit from adding PUVA
to the systemic regimen to enhance efficacy and to
reduce symptoms, such as pruritus. The most
common treatment combinations for use with
PUVA in MF are either retinoids or interferon-alfa.
However, whether combination treatments are more
efficacious than PUVA alone in early disease is still an
open question because there are few published
comparative studies.
Combination of oral retinoids and PUVA
(RePUVA) vs PUVA (level of evidence II-1)
Retinoids decrease the thickness of the
epidermis,110 enhancing UV penetration and
causing a more brisk response to UV exposure.
There are data to support the safe use of PUVA
with etretinate67 and, by extension, other retinoids,
including acitretin,111 isotretinoin,67 and bexaro-
tene112,113 in patients with MF or psoriasis. In
psoriasis, both the number of PUVA treatments and
the total amount of UVA exposure to achieve
J AM ACAD DERMATOL
n 2015
CR are decreased with the addition of an oral
retinoid to a regimen of PUVA.111 Because oral
retinoids may suppress the development of
NMSCs,114-118 their use in combination with PUVA
particularly, which increases the risk of NMSC,
appears prudent.
Combination of PUVA and retinoic acid
receptor retinoids
Thomsen et al from the Scandinavian MF Group67
treated 22 patients with early-stage MF with either
etretinate or isotretinoin and PUVA and compared
the results with 47 patients treated with PUVA alone;
there was no indication how group assignment was
determined. The response rate of RePUVA was equal
to that of PUVA, with a CR of 73% and 72%,
respectively. However, RePUVA required fewer
PUVA sessions to attain remission with a lower UVA
dosage. It appears that RePUVA could reduce the
total treatment dose of PUVA and therefore its
toxicity. The relapse rate after CR was the same after
RePUVA as after PUVA. The duration of remission,
however, seemed to be prolonged in the 8 patients
who continued retinoids as maintenance therapy
after stopping. Limitations of this study included the
study design (whether retrospective or prospective
was not clear), the fact that not all patients were
treated with the same retinoid and the doses were
not uniform (etretinate 0.3-1 mg/kg or isotretinoin
0.5-1 mg/kg), and the small number of patients who
continued retinoids as maintenance therapy.
Combination of PUVA and a retinoid X
receptoreselective retinoid, bexarotene
A number of small case series on the combination
of PUVA and the retinoid bexarotene have been
published.112,119,120 Recently the results from the
EORTC Cutaneous Lymphoma Task Force phase III
randomized clinical trial comparing bexarotene
combined with PUVA to PUVA alone in 93 patients
with stage IB to IIA MF were published in the
literature.113 No significant difference in response
rate or response duration was observed. However,
there was a trend toward fewer PUVA sessions and a
lower UVA dose required to achieve complete
clinical remission in the combination arm, but this
did not achieve statistical significance because of
insufficient power.
Combination of interferon-alfa and PUVA vs
PUVA alone (level of evidence II-1)
There are several papers on the efficacy of
interferon-alfa and PUVA in MF, stages IA to
IVB.121,122 The additional benefit of interferon and
PUVA over PUVA alone is suggested by a few case
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
series on patients refractory to previous PUVA
monotherapy who responded subsequently to this
combination.123,124 However Stadler et al125 reported
on the results of a prospective, randomized,
multicenter clinical trial on the use of interferon-
alfa plus PUVA vs PUVA monotherapy in 96 patients
with MF stages I and II. In this study, no significant
difference was found in the CR rates: combination
treatment produced a CR rate of 80% compared to
72% for PUVA alone. A recent study of pegylated
interferon-alfa 2b and PUVA vs. interferon-alfa 2a
plus PUVA showed a higher response rate in the
pegylated interferon arm.126 Interferon-alfa in
combination with PUVA has also been reported to
convert nonresponders to PUVA alone to complete
responders.123
Combination of PUVA with ECP and a biologic
agent (level of evidence II-3)
The literature regarding the role of PUVA in the
multimodality approach to treatment of erythroder-
mic MF or SS is strikingly sparse. Booken et al127
published a series of SS patients (n = 12) who were
treated with PUVA, interferon-alfa, ECP, and topical
steroids. The overall response in this retrospective
study was 42%,127 but none of the patients achieved
CR. Other reports noted the efficacy of a combina-
tion of PUVA with ECP and bexarotene, with or
without interferon-alfa or -gamma, in patients with
advanced disease.119,128 The role of PUVA in the
multimodality approach in advanced stages of CTCL
warrants additional examination.
PUVA and methotrexate
The use of methotrexate can be associated with
radiation recall, whereby patients who are taking
methotrexate who have previously received UVL or
radiation therapy experience an inflammatory reac-
tion within the previously exposed area.129 In
practice, increased photosensitivity or development
of recall erythema during the use of NB-UVB or
PUVA with methotrexate is generally not a problem.
A more significant concern with this combination is
the associated enhanced photocarcinogenesis130;
therefore, the combination of phototherapy with
methotrexate is not recommended.
Use of additional skin-directed therapy in
sanctuary sites during PUVA
Powell et al64 noted that they were able to use
topical nitrogen mustard in sanctuary areas in a
patient previously allergic to the medication while
on PUVA and noted that previous studies indicate
that PUVA may abrogate allergic skin reactions to
topical nitrogen mustard. Alternatively, handheld
Olsen et al 19
phototherapy devices and topical steroids can be
used in these areas.
Adjuvant role for PUVA after total skin electron
beam therapy
In a retrospective study published by Quiros
et al131 on 114 patients with T1 or T2 MF who were
initially treated with total skin electron beam
therapy, it was found that those patients who
subsequently received a PUVA maintenance regimen
showed an improvement in 5-year disease-free
interval compared with those who received other
forms of adjuvant therapy or those who did not
receive any additional treatment. However, there
was no staging noted beyond the skin classification
(and 22/114 had some nodal disease), no random-
ization of patients between the treatment groups,
and not all patients were clear at the time of adjuvant
therapy, making it difficult to fully assess the utility of
PUVA in this setting. There was a similar rate of NMSC
and melanoma in both groups.
NONSYSTEMIC PUVA
Topical PUVA
This refers to the application of a topical prepa-
ration of psoralen to limited body areas followed by
exposure to UVA. In practice, the commercially
available form of psoralen solution (1% 8-MOP
solution) can be diluted to a lower concentration,
usually 0.1%, with various vehicles. This should be
applied 20 to 30 minutes before UVA exposure, with
dosing reported as starting at 0.25 to 0.5/cm2 and
increasing by 0.25 to 0.6 J/cm2.132 The usual
frequency of UVA exposure is 2 to 3 times per
week. There does not appear to be any significant
systemic absorption of the topical formulation of
psoralen, and its stability is best when stored in the
refrigerator.133 Because of the high potential for
phototoxicity of the 8-MOP topical preparation, it
should be kept at the phototherapy unit and not
dispensed to the patient.
Bath PUVA
This total body treatment usually is conducted
with either trioxsalen or 8-MOP, the latter with
doses of 8-M0P in the water from 0.5 mg/L134 to
[3 mg/L.135-137 Patients sit in a tub to which psoralen
has been added for 10 to 20 minutes134-137 before
immediate exposure to UVA. In psoriasis, for clearing
purposes, bath PUVA has a much lower mean
cumulative UVA dose compared to oral PUVA.135
Although data on the efficacy of PUVA bath in MF are
limited,137-140 the results of the published studies
suggest that this modality may be a useful option
when the use of systemic PUVA is not appropriate.
20 Olsen et al
Because of the resources needed to perform bath
PUVA, it is rarely used in the United States.
Hand/foot PUVA
This is an important adjunct that can be used to
treat the tops and soles of feet that are otherwise
excluded from UVA exposure while standing in the
phototherapy box. This can be performed at the end
of the whole body treatment with systemic psoralen
on board or it can be performed at an alternate time
with prior application of topical psoralen.
UVA FOR MF/SS
UVA1
UVA1 (340-400 nm) offers certain theoretical
advantages over PUVA: it reaches deeper layers of
the dermis, broadens the type of T cell apoptosis
produced, and avoids the side effects of psoralen.5
The first publication on the efficacy of UVA1
(medium to high dose) in patients with early MF
was reported in 1999.5 All 3 cases achieved CR. In a
study published 2 years later using high-dose UVA1
(100 J/cm2), 11 of 13 patients with early-stage MF had
a CR.141 Subsequently, case reports of treatment of
granulomatous slack skin142 and hypopigmented
MF143 and a small series of early classical MF144
treated with UVA1 were published. In addition,
although PUVA is contraindicated in lupus, UVA1
has been used successfully to treat this condition.
There are, however, limitations of the use of UVA1 in
MF: it is a relatively expensive technology and is not
widely available worldwide. There have been only a
few publications of UVA1, and the long-term safety
of high-dose UVA1 is currently unknown.
BB-UVA
BB-UVA is composed of 80% UVA1 with a similar
mechanism of action. The efficacy of BB-UVA in
patients with MF was evaluated in 1 study.145 In this
comparative study of 30 patients with stage IA and IB
MF with Fitzpatrick skin phototypes III and IV, the
efficacy of high dose BB-UVA (20 J/cm2) was found
to be similar to conventional PUVA. Certainly, larger
studies are needed, including studies on patients
with Fitzpatrick skin types I and II, to establish the
role of BB-UVA in the treatment of MF.
RECOMMENDATIONS FOR
PHOTOTHERAPY OF MF/SS
Patient selection
General principles. Patients with stages IA, IB,
and IIA MF are candidates for monotherapy
with either UVB or PUVA therapy. However, thick
plaques or folliculotropic involvement may be better
served by PUVA than NB-UVB because of superior
J AM ACAD DERMATOL
n 2015
penetration of the skin with UVA. Erythrodermic MF
may be helped with either NB-UVB or PUVA alone,
but because of the preexisting cutaneous erythema,
it may be difficult in these patients to assess any
burning from the UVL and hence to safely increase
the UV dose. Patients with stage IA to IIA MF who
have failed to clear with phototherapy alone or who
have associated poor prognostic factors and patients
with stages IIB, IVA, and IVB MF/SS are best served
with UV-based therapy used in conjunction with a
systemic agent that is effective for MF/SS.
Suggestions for preliminary evaluation of the
patient with MF who is being considered for
phototherapy are shown in Table IV.
Contraindications to therapy with either NBUVB
or PUVA are outlined in Table V.
Induction, consolidation, and maintenance
Background. The goal of monotherapy with
UVL in MF, a malignant condition that may progress
off therapy, is different than that for psoriasis, a
benign condition in which the only guidelines for
UVL therapy currently exist. The goal in early MF is
always first to induce a long-lasting remission off
therapy or to at least minimize active disease with
well tolerated treatments that have little potential for
chronic toxicity. To have a long-lasting response in
MF that persists after discontinuation of the UVL, the
goal must first be a CR, defined here as 100%
clearing. It is important for third-party payers to
realize that phototherapy provides a cost-effective
means of controlling the disease, improving quality
of life, and may induce long-lasting remission in a
cancer with the potential of diminished survival for
those suffering from it, and its use in CTCL should not
be governed by the same guidelines as those for
psoriasis. To achieve 100% clearing in MF with
phototherapy and to achieve a long-lasting
remission off therapy may take longer than that in
psoriasis, depending on skin lesion type and skin
color.
There has been little consensus on the schedule of
treatments in MF with either UVB or PUVA.
Treatment during the clearance phase has the
greatest consistency among practitioners, but even
the frequency of treatment is not universally
standardized. In addition, what constitutes an
appropriate endpoint to consider stopping or cutting
back on treatment varies widely. In practice, the
frequency of treatments is often cut back before the
patient is 100% clear: sometimes this is necessary
because of difficulties with travel to the photo-
therapy unit or side effects from the treatment, but
this likely has an effect on the subsequent relapse
rate. None of the studies of NB-UVB or PUVA
J AM ACAD DERMATOL Olsen et al 21
VOLUME jj, NUMBER j

Table IV. Preliminary evaluation of patients with mycosis fungoides considered for phototherapy
History:
The following are topics to discuss with patients to determine if the patient should, and can, medically undergo
phototherapy, which type of phototherapy is most appropriate for the patient, and if, logistically and financially,
phototherapy is a feasible choice for this patient.
History of:
Nonmelanoma skin cancer or melanomadtype, site, how treated, and when
Ultraviolet lighterelated skin eruptionsdspecifics on potential triggers
Known or symptoms of photosensitivity disorders, including porphyria, lupus erythematosus, xeroderma pigmentosum,
vitiligo, etc
Burning easily upon limited sun exposure
Currently taking potential photosensitizing medications (especially relevant if PUVA is being considered)
Physical disabilities or problems precluding standing in a phototherapy booth
Transportation issues, including prolonged distance from a phototherapy center
Financial constraints
Unwillingness to forego sunbathing and tanning beds
Women of child-bearing potentialdif pregnant, planning to get pregnant, or nursing, and willingness to use
contraceptive measures during the course of phototherapy if PUVA is being considered
Physical examination:
Full skin examination, including nails, with particular reference to the following:
Actinic keratoses
Atypical pigmented lesions or multiple common nevi
Suspectednonmelanoma skin cancers or melanoma

Tests:
If patients have a history of photosensitivity, consider the following:
Blood test for antinuclear antigen(s)
MED phototesting before ultraviolet B light phototherapy and MPD phototesting before ultraviolet A light
phototherapy
Screening plasma and erythrocyte porphyrin levels if cutaneous porphyria is a possibility
PUVA only
Eye examination

MED, Minimal erythema dose; MPD, minimal phototoxic dose; PUVA, psoralen plus ultraviolet A light phototherapy.

reviewed address this question. Another place where
there is no consistency of approach to UVL
therapydand which again likely affects the relapse
ratedis in the postclearing phase, during which the
frequency and duration of continued treatment
varies widely between sites.
In order to help to develop consistent guidelines
for treatment of MF, we have created some new
terms and defined others to specifically describe the
phases of phototherapy for MF.
Induction/clearing phase. This represents the
time from when UVL is started to the time of 100%
clearing. This is the dose escalation phase, during
which the treatment frequency generally remains
the same. This term would not apply if patients are
not treated with the intent to clear. It is difficult to
determine whether a more complete definition of
clearing or whether using topical adjuvant therapy
in areas where light does not reach to induce
clearing before stopping UVL would make a
difference in the duration of remission. However,
to remove this variable from any future assessments
of response to phototherapy, there should be
assurance of complete clearing of lesions before
modification of the frequency of UV treatments. This
means a potential adjustment in treatment plans so
that all areas with lesions are either (1) exposed to
the UVL or, if not possible, (2) alternate skin-directed
therapy is used, and acknowledged, in these
sanctuary areas, or (3) consideration is given to
combination therapy with a systemic agent to ensure
that all areas are treated. Making sure that patients
know how to assume varied positions in the light
box that expose as much of the body as possible will
help to minimize these privileged sites. Most
importantly, before moving into the consolidation/
maintenance phases, clearance of lesions should
be determined by a person experienced in assessing
MF lesions in patients with various Fitzpatrick skin
types.
22 Olsen et al J AM ACAD DERMATOL
n 2015

Table V. Contraindications/cautions for of treatment. This additional time on phototherapy

phototherapy when clear may help to consolidate and extend the
Absolute Relative Caution
resulting remission.
Condition NB-UVB PUVA NB-UVB PUVA NB-UVB PUVA
Maintenance phase. Maintenance is defined
Xeroderma pigmentosa X X
here as the period of gradual decrease of frequency
Lupus erythematosus X X of UVL while in clinical remission before discontin-
Porphyria X X uation of phototherapy. The dosage of UVL should
Melanoma X X remain the same as the consolidation phase unless
Multiple nonmelanoma X X erythema occurs or erythema is anticipated to occur
skin cancers
Chronic actinic dermatitis X X
because of a given threshold of infrequency of
Claustrophobia X X treatments: in these cases, the UVL dose would
Previous arsenic intake X X need to be decreased, recognizing that the latter is
Inability to tolerate heat X X different for NB-UVB than PUVA. In general, there is
or to stand for long a commonly accepted stepwise decrease in
periods
Previous ionizing X X
frequency of UVL from 3 times a week to twice a
radiation in area of week to weekly to every 10 days and to finally every
ultraviolet radiation 2 weeks or, in the case of PUVA, possibly as
Pregnancy X* infrequently as every 3 or 4 weeks. Most centers
Lactation X reduce the frequency of UVL treatments every 4 to
Aphakia X X
Severe liver disease X
8 weeks with careful attention that the patient is still
Pediatric patients Xy X clear of lesions on physical examination before the
Immunosuppression X X next reduction in frequency. Some patients with MF,
Atypical nevi150 X X particularly those who have relapsed previously after
Multiple common nevi X x stopping UVL, may elect to continue for longer
Photosensitizing X X
medications
periods of maintenance, accepting the increased
risk of adverse effects of long-term phototherapy.
NB-UVB, Narrowband ultraviolet B light phototherapy; PUVA, The data are not clear about the value of
psoralen plus ultraviolet A light phototherapy. maintenance or the schedule of maintenance of
*Three studies of women with psoriasis who received PUVA at the either PUVA or NB-UVB in early MF. It is likely that
time of conception or during pregnancy revealed the absence of
any congenital anomalies among a total of 59 infants.151-153
prolongation of remission from UVL in stage IA MF
Although the rate of congenital malformations among 504 infants has little effect on survival, because there is an
who were conceived and born after their mothers had received excellent chance of repeat clearance with
methoxsalen photochemotherapy was not higher than that found skin-directed therapy upon relapse (either repeat
in the general population, there was an increased number of low UVL or an alternate skin-directed therapy), and these
birth weight infants who were born to these women.153 Oral
psoralen carries a pregnancy category C rating.
patients have the same prognosis as the general
y
NB-UVB appears to be safe to use in children.154 population.146 However, there is clearly a difference
in overall survival of IA from IB and IIA disease,146
Consolidation phase. With MF, clearing of and a long-lasting remission in these latter patients
clinical evidence of disease may occur without and may have a positive effect on survival. Unfortunately,
sooner than histologic clearing,19,21,24,26,57 and the data are lacking to sort this out. What is clear from
persistence of disease at the time of discontinuation the literature review, however, is that when one
of UVL may account for some of the short remissions looks just at the studies of NB-UVB in which 100%
noted. Consolidation is a term that has not been used clearance is used as an endpoint16,18,22 there appears
previously with phototherapy, but instead the term to be a decrease in the relapse rate and an increase in
maintenance has been used to cover the entire the RFI with a maintenance regimen. This certainly
period after clearing. However, consolidation here has the effect of minimizing side effects from repeat
refers to the time period after clinical clearance of courses of phototherapy and delaying the need for
lesions in which the UV dose and frequency of alternate therapy with their side effects.
treatments are both held constant. A 1-month period
of continued clearance is mandatory by research Definition of response
standards to document the presence of a CR.31 In A. Complete response (CR). In most published
clinical practice, reassessment of patients who are reports of UVB or PUVA in MF/SS to date, a clear
deemed clear at a given clinic visit should be definition of what constituted a CR is not given or,
reassessed again at $1 but #3 months later before when it is given, is often defined as \100% clearance
electing to stop or move onto a maintenance phase of disease clinically. In addition, most publications
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
do not note any timeframe in which the clearing must
have been present to be considered a documented
CR. In keeping with the definition of CR for clinical
trials of MF/SS,31 a documented CR would be one
present for $4 weeks to avoid transient responses
being reported. For the purpose of decision-making
for clinical care and clinical trials of patients
with MF or SS, obtaining a biopsy specimen is not
necessary to document clinical clearing except
in circumstances where there is a question of
whether residual pigment changes or erythema are
related to the cutaneous lymphoma or to post-
inflammatory pigmentation or erythema related to
phototherapy.
Partial response, stable disease, progressive
disease: Definitions are as previously published.31
As for CR, a documented response should be present
for $1 month.
Specifics of therapy
NBUVB.
Induction.
A. Frequency of treatments. Three times per week
on nonconsecutive days has been used most
often and should be considered standard. Three
vs. 2 times a week treatments has been shown in
psoriasis patients to clear patients significantly
more quickly.147 However, cost and transporta-
tion may define frequency of treatment and
twice weekly phototherapy will suffice to clear
the disease, albeit it at a slower pace.
B. Starting dose and incremental increases in UVL. It is
generally unnecessary to do phototesting unless
the patient has a history of sun sensitivity or the
physician wishes to use MED to direct the starting
times and incremental increases in UVB. However,
it should be noted that using the MED for directing
light therapy has been shown to lead to a higher
cumulative dose of UVL for clearing compared to
using Fitzpatrick skin type. If using MED to direct
treatment, the starting dose in most of the studies
using this for MF has been 70% of MED with
increases of 20% per session, decreasing to 10% if a
photoreaction. However, the recommendations
for MED based starting points of NB-UVB for
psoriasis generally use 50% MED with a 10%
increase per treatment for the first 20 treatments
and then additional increases left to the discretion
of the phototherapy nurse.132,148 Recommenda-
tions for initial treatment based on Fitzpatrick skin
type are given in Table VI.
C. Resumption of treatment after missed appoint-
ments. Suggestions for the resumption of
treatment after missed appointments are shown
in Table VII.
Olsen et al 23
Table VI. Treatment recommendations for
narrowband ultraviolet B light induction phase in
patients with mycosis fungoides based on
Fitzpatrick skin type*yz
Skin type Initial dose (mJ/cm2) Increments (by mJ/cm2)
I 130 15
II 220 25
III 260 40
IV 330 45
V 350 60
VI 400 65
*Data from Menter et al.132
y
If no response after 20 treatments, may increase exposure by
additional 50 to 100 mJ/cm2 above the previous incremental
increase.
z
In early-stage disease, it is generally acceptable to cover the face
during phototherapy when the face is not involved.
D. Adjustment of phototherapy caused by UV-
induced photoreactions.
1. Mild erythema (pinkness of the irradiated
skin that blanches on pressure and is not
symptomatic): no increase next treatment.
2. Moderate (skin is markedly red and
discomfort to touch, no blisters): hold until
clear, decrease next increase by 10%.
Consolidation. Dose and frequency of NB-UVB
held steady for 1 to 3 months.
Maintenance. Tapering of phototherapy can be
performed by maintaining the UVL dose given at CR
and decreasing the frequency of treatments gradu-
ally before stopping (Table VIII). The minimal time
necessary to come from 2 to 3 times per week to
stopping UVL for most centers/studies appears to
3 months. Patients undergoing NB-UVB therapy may
not be able to tolerate treatments given less
frequently than every 10 days without a significant
reduction in amount of UVL. The decision to have a
prolonged maintenance period is best determined
by weighing the risk factors of chronic NB-UVB vs.
the cost (ie, psychological, time, and cost) of a
clinical relapse with the potential need to restart
therapy at frequency of 3 times per week.
PUVA.
Induction.
A. Psoralen. The recommended dose of 8-MOP is
0.6 mg/kg with UVA exposure 2 hours later and
Oxsoralen-Ultra 0.5 mg/kg with UVA exposure 1
to 1.5 hours later. The usual precedent is to
round down when optimum dosing would be
between 2 doses.
B. Frequency of treatments. The optimum spacing
of treatments for PUVA is at least 48 hours
24 Olsen et al J AM ACAD DERMATOL
n 2015

Table VII. Resumption of treatment after missing Table IX. Treatment recommendations for
scheduled treatment visits for mycosis fungoides psoralen plus ultraviolet A light phototherapy
during the induction phase* induction phase in patients with mycosis fungoides
Time between treatments NB-UVB PUVA
based on Fitzpatrick skin type*yz
4-7 days Dose the same Dose the same Skin type Initial dose (J/cm2) Increments (by J/cm2)
8-14 days Decrease by 25% Decrease by 25% I 0.5 0.5
15-21 days Decrease by 50% Decrease by 50% II 1.0 0.5
22-28 days Start over Decrease by 75% III 1.5 1.0
[4 wks Start over Start over IV 2.0 1.0
V 2.5 1.5
NB-UVB, Narrowband ultraviolet B light phototherapy; PUVA, VI 3.0 1.5
psoralen plus ultraviolet A light phototherapy.
*Data from Menter et al132 and Zanolli et al.148 *Data from Menter et al132 and Zanolli et al.148
y
If no response after 20 treatments, increase exposure by
additional 0.5 to 1 J cm2 above the previous incremental
Table VIII. Maintenance phase treatment of increase. Patients with erythroderma must be treated cautiously
patients with mycosis fungoides with ultraviolet and treatments should be spread out or lower increments of
light (based on a thrice-weekly induction schedule increase over last treatment used if any pain, stinging, or increase
in erythema occurs.
for narrowband ultraviolet B light phototherapy z
In early-stage disease, it is generally acceptable to cover the face
and at least twice weekly for psoralen plus during phototherapy when the face is not involved.
ultraviolet A light phototherapy)*y
NB-UVB PUVA
Dose E. Adjustment of phototherapy because of
Treatment Dose relative relative to
frequency Weeks to end consolidation Weeks end consolidation UV-induced reactions. These adjustments mirror
Twice weekly 4-8 Same 4-8 Same those for NB-UVB reactions.
Weekly 4-8 Same 4-8 Same
Every 10 days 4-8 Same 4-8 Same Consolidation. The dose and frequency of UVR
2 wks* 4-8 Decrease by 25% 4-8 Same are held steady.
3 wks NA Decrease by 50% 4-8 Same Maintenance. Tapering can be performed by
4 wks NA NA 4-8 Same maintaining the UVA dose given at CR and
decreasing the frequency of treatments gradually
NA, Not applicable.
*Recommended treatment after complete response before stopping (Table VIII). The minimal time
is $ 3 months, including a consolidation period with complete necessary to come from 2 to 3 times per week to
response being documented before transitioning to less frequent stopping UVA for most centers/studies appears to
treatments. 3 months, with 6 months being cautionary. The
y
Adapted from Zanolli et al.148
decision to have a prolonged maintenance period is
(but preferably 72 hours). Treatments for MF best determined by weighing the risk factors of
given more frequently than twice per week will chronic PUVA vs. the cost (ie, psychological, time,
shorten the number of exposures and time to and cost) of a clinical relapse with the potential need
clearing, but a study of psoriasis patients treated to restart therapy at frequencies of 2 to 3 times per
with PUVA using Fitzpatrick skin type to estab- week.
lish starting dose found no significant difference
in the number of treatments to clearance or in Clinical trial
cumulative UVA dose between 2 and 3 times In future clinical trials, controlling for as many of
weekly regimens.149 Given the desire to deter- the variables of phototherapy as possible by stan-
mine any photoreactions from the last treatment dardizing practices will facilitate comparison of
before the current PUVA treatment, a cautious results across trials and help determine best practices
approach would be twice weekly treatments. for patients with MF. In many cases, phototherapy
C. Starting dose and incremental increases in UVL. will be involved as a comparator/active treatment
Recommendations for the starting UVL dose arm in a clinical trial, either as monotherapy in
based on Fitzpatrick skin type are shown in early MF or part of combination therapy with a
Table IX. systemic agent for more aggressive or later stage MF.
D. Resumption of treatment after missed The important variables to standardize for trials are:
appointments. Suggestions for the resumption (1) induction period parameters of frequency of
of treatment after missed appointments are treatment, escalation of dose of UVL, and dose of
shown in Table VII. psoralen if PUVA is the type phototherapy used; (2)
J AM ACAD DERMATOL Olsen et al 25
VOLUME jj, NUMBER j

Table X. Information on narrowband ultraviolet B light phototherapy for patients with mycosis fungoides and
S

ezary syndrome
Background: NB-UVB is a part of the ultraviolet B spectrum, which has a peak output at 311-312 nm. Data have shown that
the efficacy of NB-UVB approximates that of PUVA for patches and thin plaques of MF.
Frequency of treatments: Treatments are usually given 3 times a week with $24 hours between treatments. Twice-weekly
treatment is also reasonable, although it will take longer to clear with less frequent treatment.
Time to response: You will typically see a response within 1 month of treatment.
Duration of treatment: It is recommended that you remain at the frequency of treatment you start with until you clear, and
then the frequency of treatments will be gradually decreased. Your doctor will then determine if it is best for you to
continue with a long-term maintenance regimen.
Position in the light box: It is important to try to expose all areas to the light. This may mean that you will need to assume
certain positions to expose your underarms, sides of trunk, inner thighs, under breasts in women, and tops of feet. Your
doctor or phototherapy nurse will show you how to do this so that you do not burn from having various parts of your
body closer to the light than others. Your doctor may also suggest that you stand on a short platform in order to better
treat the bottom of your legs.
Most common potential side effects of NBUVB
Short-term: Skin redness; discomfort; feeling faint in the light box (heat is generated during the light treatmentdif you
have a history of heat intolerance, heart disease, or claustrophobia, please let your doctor know before the decision to
pursue light therapy is made).
Skin cancer: Repetitive exposure to ultraviolet light increases your risk of nonmelanoma skin cancer (ie, squamous cell carcinoma
and basal cell carcinoma); however, there is no evidence for a specific increase after NB-UVB. If you have had previous skin
cancers, you are at higher risk of getting more of them, with or without NB-UVB. Your doctor will help to ensure that before you
have NB-UVB, that any skin lesion suspicious for cancer has been addressed. As skin cancer may be a delayed risk, all patients
treated with ultraviolet light should be monitored yearly for the early detection of new skin cancers.
Pigmentation: Tanning is part of the expected effects of NB-UVB.
Aging: Long-term NB-UVB, like excessive sun damage, will accelerate the aging of your skin with increased wrinkling.
Instructions for safe use of NBUVB
Skin protection
Oils should not be applied before NB-UVB treatment unless your doctor specifically recommends that you put this
on selected areas and that you plan to do this before each treatment.
Each time you get NB-UVB, your phototherapy nurse will calculate that days light dosage based on your last
treatment time and whether you had any redness after the treatment. Please be sure to report any redness or
discomfort you may have experienced to the phototherapy nurse before each treatment.
Sunscreen use
On the day of phototherapy, do not apply sunscreen before NB-UVB exposure either as part of your normal skin care
regimen or with the intent of protecting areas that became red at the last visit. To do so may set up areas on the
body that are less tolerant to the NB-UVB treatment and could on subsequent sessions if inadvertently exposed,
produce burning. In addition, sunscreen will exclude areas of the body from treatment for your MF. Your doctor
may recommend, however, that sunscreen be applied to areas that are meant to be totally excluded from light
exposure, such as the face in those patients without any facial involvement, although there are other means of
shielding these areas that are more protective.
Sunscreen with an SPF of $30 should be applied on days not receiving NB-UVB and after phototherapy. Please
remember to reapply your sunscreen every 2-3 hours during prolonged outdoor time.
Shielding certain areas
Men should shield their genitals while in the light box by either wearing an athletic supporter or a sock: if the former,
then the waist strap needs to be moved around each time so that all areas of the nongenital skin are treated.
Women may shield their nipples with a broad spectrum sunscreen (SPF [50) or a physical blocker, such as zinc oxide
paste. To avoid burning on subsequent treatments, the entire areola should be carefully covered.
Any areas of recent skin cancer or new surgical scars should be shielded from light exposure.
If no facial lesions are present, patients may elect to shield their faces with a towel or bag.
No sun tanning or tanning beds should be used during any time NB-UVB is being used to treat your MF because it
can affect the amount of ultraviolet B light you receive during treatments. Suntanning and tanning beds should
not be used after you complete your course of NB-UVB because they are an added risk for the development of skin
cancer. If you are unwilling to forego sunt anning or tanning bed use, let your doctor know before you start NB-UVB.
Patients treated with NB-UVB should minimize purposeful exposure to sunlight once NB-UVB therapy has been
completed.
Follow-up: Regular evaluation by your dermatologist during NB-UVB and annual skin examinations are recommended.
MF, Mycosis fungoides; NB-UVB, narrowband ultraviolet B light phototherapy; PUVA, psoralen plus ultraviolet A light phototherapy.
26 Olsen et al J AM ACAD DERMATOL
n 2015

Table XI. Information on psoralen plus ultraviolet A light phototherapy for patients with mycosis fungoides
and S

ezary syndrome
Background: PUVA is an acronym for the medication psoralen (P) plus ultraviolet A light (UVA) and has been used to treat MF
since 1979. Psoralen is necessary to minimize the time in the light box for the patient to get the full effect of the UVA.
PUVA is also used to treat psoriasis.
Medication: There are 2 types of oral psoralen: Oxsoralen-Ultra should be taken 1-1.5 hours before exposure to UVA and 8-
methoxypsoralen (8-MOP) 2 hours before UVA exposure. The dose of psoralen is based on your weight, so if you lose or
gain weight, please inform your doctor or nurse overseeing the PUVA treatments. Patients may have nausea with the
psoralen that can be minimized by taking with milk, crackers, or a meal: if you do this, please try to do the same thing
each time you take the psoralen so that your resulting blood level of psoralen is the same each time you have your light
therapy because food affects (decreases) psoralen absorption. Rarely, patients need to take an antinausea pill 30-60
minutes before taking psoralen.
Frequency of treatments: Treatments are usually given 2-3 times a week with at least 48 hours between treatments, the
latter because it takes at least 48 hours to see any sunburn reaction to PUVA. The subsequent dosage of light/time in
the light box will be adjusted if there is redness from the previous PUVA treatment.
Time to response: You will typically see a response within 1 month of treatment.
Duration of treatment: It is recommended that you remain at the frequency of treatment you start with until you clear and
then the frequency of treatments will be gradually decreased. Your doctor will then determine if it is best for you to
continue with a long-term maintenance regimen.
Position in light box: It is important to try to expose all areas to the light. This may mean that you will need to assume
certain positions to expose your underarms, sides of trunk, inner thighs, under breasts in women, and tops of feet. Your
doctor or phototherapy nurse will show you how to do this so that you do not burn from having various parts of your
body closer to the light than others. Your doctor may also suggest that you stand on a short platform in order to better
treat the bottom of your legs.
Most common potential side effects of PUVA
Short-term: Skin redness, discomfort, blisters like various degrees of a sunburn; nausea after taking psoralen; feeling faint
in the light box (heat is generated during the light treatment: if you have a history of heat intolerance, heart disease, or
claustrophobia, please let your doctor know before the decision to pursue light therapy is made). Please tell your
phototherapy nurse if you experience any of these in the interval since last treatment.
Skin cancer: There are data that prove an increased risk of nonmelanoma skin cancer (ie, squamous cell carcinoma and
basal cell carcinoma) and possibly melanoma with PUVA. There are certain risk factors for both and not all patients are at
the same risk: the risk of melanoma is low under 100 PUVA treatments and higher when given 200-400 treatments. Your
doctor will discuss potential risk factors for these and will help you to insure that before you have PUVA, that any skin
lesion suspicious for cancer has been addressed. Because skin cancer may be a delayed risk, all treated patients should
be monitored yearly for the early detection of new skin cancers.
Pigmentation: You may develop some permanent brown spots during PUVA called PUVA lentigosdthese are benign. You
may also have other types of lesser or greater pigmentation in the skin most of which are reversible off therapy. You will
develop a tan if you have light skin. If you are dark-skinned, your skin tone will deepen and it is possible that your nail
beds will also have increased pigmentation.
Eye: There is a potential risk of cataracts if adequate eye protection is not carried out after taking psoralen. See directions
below.
Aging: PUVA given over time will accelerate the aging of your skin with increased wrinkling.
Instructions for safe use of PUVA
Eyes
Before you begin PUVA, your doctor will want to insure that you have had a thorough eye examination (including retinal
and visual field examination) within the past 6 months and that any abnormalities are specifically noted. You will be
asked to have a repeat eye examination 1 year after starting PUVA, but may have this sooner if there are new
complaints or findings. Please let your doctor know if during the course of PUVA treatments you experience any new
eye changes.
Because psoralen taken orally will reach all body tissues, including your eyes, it is important to protect your eyes from
ultraviolet light during the 24 hours the medication is in your system. After you take your dose of psoralen, and for the
next 24 hours, if you go outside or if you sit by a window (UVA will come through window glass), you should wear
protective glasses with a side shield that specifically protects against the UVA wavelength of light. Your doctor can
recommend these glasses or you can get these at an optometrists/ophthalmologists office but if the latter, the
glasses must specifically protect against UVA. If your eyes are not protected from UVA exposure at the critical time
period, this could lead to cataracts.
During the PUVA treatment itself, you will be given UVA-protective goggles to wear.
Continued
J AM ACAD DERMATOL Olsen et al 27
VOLUME jj, NUMBER j

Table XI. Contd

Women of child-bearing potential
PUVA is best avoided during pregnancy or nursing. If you are considering trying to get pregnant in the near future or are
pregnant or nursing, you should not begin PUVA. Women of child-bearing potential should be using effective birth
control during the entire course of PUVA.
Skin protection
Fragrances should not be applied to the skin when getting PUVA because some are photosensitizing. Oils should not be
applied before PUVA treatment unless your doctor specifically recommends that you put this on selected areas or that
you do this regularly each time.
Sunscreen use
Suncreens should not be used on the day of PUVA before treatment.
Do not apply sunscreen immediately before UVA exposure with the intent to protect areas that became red at the last
visit. To do so may set up areas on the body that are less tolerant to the PUVA treatment and could on subsequent
sessions if inadvertently exposed, produce burning. In addition, applying sunscreen to certain areas excludes those
areas of the body from treatment for your MF. Your doctor may recommend, however, that sunscreen be applied to
areas that are meant to be totally excluded from light exposure, such as the face in those patients without any facial
involvement with MF, although there are other means of shielding these areas that are more protective.
Broad spectrum sunscreen, which protects against UVB and UVA and with an SPF of $30, should be applied anytime
you are going outside or sitting in front of window glass (car rides are important here to consider) with exposed skin
both after your PUVA treatment and on days you will not be going in for a PUVA treatment. This should be a
sunscreen labeled as broad spectrum. Please remember to reapply sunscreen every 2-3 hours during prolonged
outdoor time.
Always communicate your use of sunscreen with the nurse or technician giving the light treatment.
Patients treated with PUVA should minimize purposeful exposure to sunlight once PUVA therapy has been completed.
Men should shield their genitals while in the light box by either wearing an athletic supporter or a sock: if the former, then
the waist strap needs to be moved around each time so that all areas of the nongenital skin are treated.
Women may shield their nipples with a broad spectrum sunscreen (SPF [50) or a physical blocker, such as zinc oxide
paste. To avoid burning on subsequent treatments, the entire areola should be carefully covered.
Any areas of recent skin cancer or new surgical scars should be shielded from light exposure.
If no facial lesions are present, patients may elect to shield their faces with a towel or bag.
For 24 hours after PUVA, no sunlight exposure should occur. Patients who must be outside for any amount of time during
this time period should wear protective clothing and sunscreen (an SPF $30 that is labeled as broad spectrum) on
exposed areas, including the hands and face. A broad-brimmed hat should be worn as well. If driving, the sunlight
coming through the window can be a problem and sunscreen and protective glasses become extremely important
during this time period. Commercially available window films (Llumar, 3M, and others) that block UVA can be applied to
the window glass if necessary.
No sun tanning or tanning beds should be used during any time PUVA is being used to treat your MF as it can affect the
amount of UVA you receive during treatments. Sun tanning and tanning beds should not be used after you complete
your course of PUVA because they are an added risk to skin cancer. If you are unwilling to forego these, let your doctor
know before you start PUVA.
Follow-up: Regular evaluation by your dermatologist during PUVA and annual skin examinations are recommended.

MF, Mycosis fungoides; NB-UVB, narrowband ultraviolet B light phototherapy; PUVA, psoralen plus ultraviolet A light phototherapy.

the duration of consolidation; and (3) the minimal Concomitant medications

time period of maintenance. The total UV dose
(J/cm2 or mJ/cm2), much like that given for radiation
therapy, should be given in any publication in
which the results of phototherapy for patients with
MF are reported. Definitions of response should be
as standardized as in the ISCL/EORTC/USCLC
guidelines.31
PATIENT EDUCATION AND SAFETY
Specific recommendations and potential hand-
outs for patients for both NB-UVB and PUVA are
given in Tables X and XI.
There are many medications that are inherently
photosensitizing. These include medications
used to treat MF, such as retinoids, or medications,
such as the tetracyclines and hydrochlorthiazide
(and the thiazide-like diuretic furosemide), that are
used to treat medical conditions other than
cutaneous lymphoma. Generally, medications
increase photosensitivity to UVA and rarely UVB.
Therefore, the concern for phototoxicity is greatest
with PUVA rather than NB-UVB therapy. The best
scenario is that the potentially offending medication
is stopped or substituted before UVL is begun or at
least started before phototherapy is initiated: in the
28 Olsen et al
latter case, at least the patients sensitivity to UVL can
be accommodated from the first treatment going
forward and more gradual incremental increases of
UVL instituted as necessary. However, if a patient
begins $1 of these medications during the course of
phototherapy, one should be vigilant about an
increased potential for phototoxicity at doses of
UVL that up until then have been well tolerated,
and make adjustments to treatment dose as
necessary; this may include lowering the UVA dose
or a slower rate of incremental increases in UVA.
Specifically as pertains to retinoids, if started after
phototherapy has begun, one should err on the side
of caution and decrease the dose of UVL to one-third
to one-half of what the patient is receiving at that
time, and increase the dose more slowly afterwards.
As a general rule, it is advised that potentially
photosensitizing medications should be taken after
the UVL session, if possible.
SUMMARY
Phototherapy is one of the key treatments for MF,
either as monotherapy for those with early-stage
disease or as part of a multimodality regimen for
those with more extensive or resistant disease. The
immediate relief that many patients get both in terms
of decrease in lesion size and/or number or in
pruritus with phototherapy is gratifying. However,
data necessary to determine the best regimen for
phototherapy in terms of both long term efficacy and
safety in patients with MF/SS have been lacking
because of the lack of standardization of therapy.
These guidelines, based on both literature review
and expert opinion, have been developed to offer
assistance to both clinicians treating these patients
and investigators designing clinical trial protocols
that involve phototherapy. Having standardized
protocols for phototherapy should facilitate the
analysis of treatment results and ultimately improve
patient outcomes.
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