626686

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CMSXXX10.1177/1203475415626686Journal of Cutaneous Medicine and SurgeryBesner-Morin et al

Original Article

Journal of Cutaneous Medicine and Surgery

Tazarotene 0.1% Cream as 1­–5

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DOI: 10.1177/1203475415626686

Cutaneous T-Cell Lymphoma jcms.sagepub.com

Catherine Besner Morin1,2, David Roberge1,2,3, Irina Turchin4,

Tina Petrogiannis-Haliotis1,3, Gizelle Popradi1,3, and Kevin Pehr1,3

Abstract
Background: Numerous treatments are available for cutaneous T-cell lymphoma (CTCL), including systemic retinoids. Very
few data are available on topical retinoids.
Objectives: The aim of this study was to evaluate the safety and efficiency of tazarotene as monotherapy for early-stage
CTCL.
Methods: An open-label, prospective study of tazarotene as monotherapy for stages IA to IIA CTCL was conducted. Index
lesions on 10 patients were followed for 6 months on treatment, plus at least 6 months off treatment.
Results: Six patients (60%) showed complete response (CR). Erythema, scaling, thickness, and lesion area decreased
progressively throughout treatment. The mean time to CR was 3.8 months; CR was durable for at least 6 months in 83%.
Of the 4 patients (40%) without CR, 2 (20%) had stable disease and 2 (20%) stopped the medication because of local side
effects; none showed progression.
Conclusions: This is the first Canadian trial providing evidence that topical tazarotene has excellent potential as a
monotherapy agent for stages I to IIA CTCL.

Keywords
dermatology, retinoids, cutaneous lymphoma, CTCL, tazarotene

Introduction instead of bexarotene. First, bexarotene is not available in

Cutaneous T-cell lymphoma (CTCL) comprises a heteroge-
neous group of T-cell non-Hodgkin lymphomas primarily
involving the skin. Its annual incidence is estimated to be as
high as 11 cases per million. Classic mycosis fungoides
(MF) is the most frequent type of CTCL, encompassing
approximately 59% of all CTCL cases and 44% of all cuta-
neous lymphomas. It occurs predominantly in white, mid-
dle-aged men.1-4 A wide range of treatments are available,
characterized as either skin directed or systemic. Retinoids
are biologic response modifiers that have antiproliferative,
antiangiogenic, and immunomodulatory effects. The effi-
cacy of systemic retinoids in the management of MF and
other forms of CTCL is well established.5-7 Bexarotene gel,
a topical formulation of a retinoic X receptor–selective reti-
noid, was used for the treatment of stages I to IIA CTCL
with good results in a limited number of studies.8-10 A single
US study by Apisarnthanarax et al11 suggested that another
third-generation retinoid, tazarotene 0.1% gel, could be an
effective and well-tolerated adjunct therapy for refractory
MF lesions. There are 2 advantages to using tazarotene
many countries, including Canada. Second, where avail-
able, such as in the United States, it is prohibitively expen-
sive, costing more than $13,000, compared with $600 for
tazarotene cream (http://www.goodrx.com, accessed March
30, 2015).
In this study, we evaluated tazarotene 0.1% cream
(creams generally being less irritating than gels) as a sin-
gle agent in patients with stages I to IIA CTCL. We
hypothesized that this formulation could significantly
decrease clinical findings of CTCL while maintaining an
acceptable side-effect profile.
1
McGill Multidisciplinary Cutaneous Lymphoma Clinic, Jewish General
Hospital, McGill University, Montreal, QC, Canada
2
Université de Montréal, Montreal, QC, Canada
3
McGill University, Montreal, QC, Canada
4
Fredericton, NB, Canada
Corresponding Author:
Kevin Pehr, MD, McGill University, 780-4060 Ste Catherine W,
Westmount, QC H3Z2Z3, Canada
Email: pehrkevin@sympatico.ca
2 Journal of Cutaneous Medicine and Surgery 
Table 1.  Physician’s Global Assessment of Clinical Condition.
Response Description (All Refer to Response of Index Lesion)
Complete response No clinical evidence of disease (100% improvement)
Partial response Significant improvement (decreased by 50% to <100%)
Stable disease No change (0%) or slight improvement (<50%) or slight increase in AILDS score or index surface area, but ≤25%
Progressive disease Worse than baseline by >25%
Note. AILDS, Assessment of Index Lesion Disease Severity.
Methods
Study Design
We conducted an open-label, prospective study to evaluate
tazarotene 0.1% cream as monotherapy treatment for stages
IA, IB, and IIA CTCL. For each patient, an index lesion was
selected by consensus of the patient and the treating physi-
cians as being typical of that patient’s lesions, being easily
accessible for self-treatment, and being easily visible and mea-
surable for monitoring. Patients were recruited at the McGill
Multidisciplinary Cutaneous Lymphoma Clinic at Jewish
General Hospital in Montreal, Quebec, Canada. Informed con-
sent was obtained from all patients. The study was approved
by the McGill University institutional review board and con-
formed to the Declaration of Helsinki.
Selection Criteria
Inclusion criteria were age > 18 years and a diagnosis of stage
IA, IB, or IIA CTCL. Women of childbearing potential were
required to demonstrate negative results on a pregnancy test
before enrollment and to agree to use 2 effective methods of
contraception during the study. Exclusion criteria were higher
stage CTCL; pregnancy; childbearing potential and inability
or unwillingness to use 2 effective methods of contraception;
treatment with topical retinoid therapy within 3 months of
enrollment; treatment with systemic isotretinoin or bexaro-
tene within 3 months before the study start date; use of sys-
temic acitretin within 2 years before the study start date or
any other systemic CTCL therapy, including systemic corti-
costeroids, within 30 days of the study start date; and use of
any known photosensitizing medications.
Baseline Assessment
After enrollment, patients underwent complete histories and
physical examinations to determine their baseline status. The
index lesion was measured and the outline traced using a
VISITRAK Grid (Smith & Nephew Canada).
Treatment Algorithm and Follow-Up
Patients were directed to apply tazarotene 0.1% cream to the
index lesion on alternate days for the first 2 weeks and then
to increase to once-daily application, if tolerated. In case of
irritation, patients were told to stop tazarotene application
until resolution of the signs and symptoms and resume 2 or 3
applications per week for 2 weeks, escalating to every other
day or daily as tolerated.
Patients were followed bimonthly with focused physical
and lymph node examinations, body surface area (BSA)
assessment, and photography and mapping of the index
lesion. Side effects were recorded during these visits.
The treatment protocol specified 6 months on treatment
with a follow-up of at least 6 months after treatment cessation.
Assessment of Clinical Efficacy and Response
Clinical efficacy was evaluated bimonthly using Physician
Global Assessment (PGA) and Assessment of Index Lesion
Disease Severity (AILDS) scores.
The PGA score represented the investigator’s assessment
of improvement or worsening in overall disease compared
with baseline (Table 1). A complete response (CR) required
100% improvement with no clinical evidence of residual dis-
ease (histologic confirmation was not required). Partial
response (PR) was defined as significant improvement (50%
to <100%). Progressive disease (PD) was defined as a ≥25%
increase in AILDS ratio and a ≥25% increase in the index
surface area. Finally, stable disease (SD) was defined as dis-
ease not meeting PR, CR, or PD criteria.
The AILDS score was based on the index lesion disease
severity scoring at each visit compared with baseline. The
scoring was calculated as severe (3 points), moderate (2
points), mild (1 point), or not evident (0 points) for erythema,
scaling, and plaque elevation (as judged by consensus of treat-
ing physicians), whereas index surface area was calculated
with the help of VISITRAK Grid.
The primary end point was based on PGA score, and
response was deemed favorable if the patient met PGA crite-
ria for CR or PR after 6 months of therapy. Treatment was
considered to have failed if a patient demonstrated SD or PD
at 6 months or if the patient completely stopped treatment
because of side effects. Secondary end points included eval-
uation of disease severity on the basis of AILDS score (ery-
thema, scaling, elevation, and index surface area) over time,
response duration (relapse time), and assessment of side
effects and overall tolerability of tazarotene 0.1% cream.
Adverse effects such as pain, pruritus, burning, ery-
thema, and fissuring were inquired about at each follow-up
Besner-Morin et al 3

Table 2.  Clinical Response Shown by Number of Patients.

Outcome n (%)
Clinical response  
  Complete response 6 (60)
  Partial response 0 (0)
 Total 6 (60)
Failure  
  Stable disease 2 (20)
  Progressive disease 0 (0)
  Withdrew because of side effects 2 (20)
 Total 4 (40)
Total 10 (100)

visit. Serious adverse events were defined as any adverse Figure 1.  Change in mean grades of index lesions according to
events that resulted in any of the following outcomes: the Assessment of Index Lesion Disease Severity scoring system
death, life-threatening adverse events, persistent or signifi- at 0, 2, 4, and 5 months.
cant disability or incapacity, required inpatient hospitaliza-
tion or prolonged hospitalization, and congenital anomaly
or birth defect.

Results
Of the initial 13 patients enrolled in this study, 10 were eval-
uable. Of the 3 patients not considered, 2 were lost to follow-
up after the initial visit, and 1, upon expert review of the
biopsy specimen, was deemed not to have MF. The majority
were men (80%), and the mean age was 54 years (range,
23-71 years). The majority were Caucasian (80%), with 1
patient (10%) each of African and Middle Eastern descent.
Clinical results are shown in Table 2. Of the 10 evaluable
patients, 6 (60%) had CR (confidence interval, 0.31-0.89),
none had PR, and 4 (40%) experienced treatment failure.
Among patients considered to have responded positively, all
6 showed CR at 6 months of treatment. Overall, the mean
time to CR was 3.8 months. One patient’s (17%) index lesion
disappeared completely before the first follow-up visit, 2
(33%) had CR by their second follow-up visits, and 3 (50%)
had PR during their first follow-up visits and had cleared up
by the last follow-up visit, 4 to 6 months after the start of
treatment. Of the 4 patients (40%) in whom treatment failed,
2 (20%) stopped taking the medication because of side
effects, whereas the other 2 (20%) showed no or inadequate
improvement (SD). No events of PD occurred.
Changes in the index lesion over time for the 8 patients
who completed the 6 months of treatment are depicted in
Figure 1. Each line represents 1 component of the AILDS
score. Values of the curves (y) represent the sums of indi-
vidual scores in that particular category at the follow-up vis-
its, expressed as percentages. As shown, erythema decreased
by a total of 63% and scaling by 86%. All index lesions were
deemed to have no component of “plaque elevation” after 6
months on tazarotene. Application of the tazarotene cream
resulted in marked diminution of index lesion total surface
area, by 59% (Figure 2).
Figure 2.  Index lesion at baseline (a) and after 6 months of
treatment (b). Hypopigmentation after inflammation can be seen
in (b). (Biopsy scars are visible.)
All patients with CR after 6 months of treatment were
reassessed off treatment for at least 6 months (5 of the 6
patients at 6 months; the sixth patient had moved away but
returned after 13 months for reassessment). The relapse rate
was 16.6%; 1 of the patients had recurrence of MF lesions
after 6 months off tazarotene. Therefore, 5 of 6 patients
(83.3%) were still experiencing complete clearance at least 6
months after the end of therapy, including the patient evalu-
ated at 13 months.
The majority of patients in this study (70%) experienced
mild treatment-related side effects, such as pruritus, burning,
erythema, and desquamation, as are commonly seen with
topical retinoids. No major adverse events were reported,
and no patients developed allergic contact dermatitis. Two
patients decreased the frequency of application to every sec-
ond day to manage the side effects, thereby allowing them to
successfully complete 6 months of treatment. Withdrawal
from the study because of side effects was significant (20%),
considering the small population studied. An important
caveat is that both patients withdrew before the first follow-
up visit, hindering the possibility to counsel them to reduce
4 Journal of Cutaneous Medicine and Surgery 
the frequency of application. Of note, of the 3 patients who
experienced no side effects throughout the 6 months of treat-
ment, 2 were evaluated as not reaching clinical response
(SD). Of all patients experiencing side effects, 86% reported
burning, pruritus, and increased erythema at the first follow-
up visit, 2 months after the start of tazarotene. All adverse
effects were grade 1 or 2 (mild or moderate) according to the
Cancer Therapy Evaluation Program Common Terminology
Criteria for Adverse Events.12
Discussion
CTCL is a chronic condition, and treatments focus on the
alleviation of symptoms and maintenance of relapse-free
survival.4 A number of treatments are already available com-
mercially, but many have significant side effects, including
skin atrophy, aging, and secondary cutaneous malignancies.
Moreover, patients can develop resistance with long-term
use of some treatments. Thus, there is an ongoing need to
develop novel topical treatments for this disease.
Retinoids can bind to the nuclear retinoic acid receptor or
retinoic X receptor, inhibit cell growth by arresting cells in
the G1 phase of the cell cycle, induce apoptosis in tumor
cells, and upregulate antigen presentation by Langerhans
cells and tumor cell surface expression of human leukocyte
antigen–antigen D related, CD11c, β-integrin, and interleu-
kin-2, all of which are involved in T-cell activation.7,13-17
Retinoids also enhance interferon-γ production, resulting in
downregulation of T helper 2 cells (which are increased in
advanced-stage CTCL) and upregulation of T helper 1 cells
cells.18,19
The efficacy of topical retinoids for the treatment of
CTCL has been under investigation since the early 2000s.7-11
Preliminary results are encouraging, although only a few tri-
als have been published. The most important series are those
of Breneman et al,9 who evaluated bexarotene in 67 patients
with early-stage MF, with CR and PR in 21% and 42% of
patients, respectively, and Heald et al,10 who conducted a
phase 3 trial of bexarotene gel in 50 patients with early-
stage CTCL, with an overall response rate of 44%.
Tazarotene is a retinoic acid receptor–β/γ agonist. It is a pro-
drug metabolized by the skin into the active form. As noted
earlier, tazarotene costs only a fraction of the price of bex-
arotene. To date, only 1 study, by Apisarnthanarax et al,11
has investigated the use of topical tazarotene 0.1% as a gel
as adjunctive therapy for early patch or plaque CTCL lim-
ited to <20% BSA.
In this study, we found that topical tazarotene as a cream
has excellent potential as monotherapy for early-stage
CTCL. Our results are in general agreement with previous
findings by Apisarnthanarax et al,11 but particular differences
are noted. First and foremost, our study used tazarotene as
monotherapy, not an adjunct. Second, Apisarnthanarax et al
reported that 11 of 19 patients (58%) achieved at least a
moderate (>50%) global improvement in BSA, with only
35% showing CR. Our results showed a similar 60% response
rate, but in our study, all patients who responded demon-
strated CR by 6 months; there was no PR in our patients. This
difference may be explained by the fact that our minimal
time of treatment was 6 months, as opposed to 12 weeks in
the previous study. Indeed, half of our patients showed only
PR to the medication until their final follow-up visits.
Of the 3 patients who reported no side effects throughout
the 6 months of treatment, 2 were evaluated as not reaching
clinical response (SD). As is common with topical retinoids,
efficacy is often accompanied by mild irritation. It is possible
that the 2 patients who had SD and no side effects were not
as adherent to treatment.
Overall, the AILDS score, including total surface area,
decreased significantly. Each component decreased progres-
sively over the 6 months, reinforcing the concept that this
period reliably assesses the full treatment potential of tazaro-
tene cream. However, after the initial 2 months, neither the
erythema nor the total surface area was significantly reduced.
One possible explanation could be that retinoids yield an
appearance and symptoms due to local irritation that are sim-
ilar to CTCL, notably pruritus and erythema. Prolonging
treatment allows the distinction of true residual lesions from
irritant dermatitis.
Limitations of this study include a small sample size, a
lack of histologic controls, and an open study design.
Although tazarotene 0.1% cream was generally well toler-
ated, mild to moderate local cutaneous irritation was observed
in 70% of patients, including the 2 patients (20%) who with-
drew from the study because of these cutaneous side effects.
Trials with bexarotene and tazarotene demonstrated the prac-
tical limitations of gel application over large BSAs and the
tolerability of irritant dermatitis, a limiting factor when
assessing the appropriateness of retinoids as the choice of
treatment. Skin irritation in our cohort (70%) was slightly
less than previously reported by Apisarnthanarax et al11
(86%) and in the phase 3 bexarotene gel trial10 (94%).
Although local irritation is a nearly inevitable side effect
with the use of topical retinoids, most patients continued
treatment without any modification to the regimen and did
not need corticosteroids to palliate side effects.
Conclusions
This is the first study showing that topical tazarotene 0.1%
cream has excellent potential as monotherapy for stages I to
IIA CTCL. The cream needs to be applied for 6 months
before judging its efficacy, as patients may still improve
from PR to CR after 4 months. This study demonstrates pro-
spectively, for the first time, that topical tazarotene has
greater potential as a treatment than previously reported.
Limitations of this study include a small sample size and the
fact that we used an open-label design.
Besner-Morin et al 5
Acknowledgments
Tazarotene cream was graciously provided by Allergan Canada,
which had no role in the design and conduct of the study; collection,
management, analysis, or interpretation of the data; preparation,
review, or approval of the manuscript; or decision to submit the
manuscript for publication. This research has not been presented at
any previous conference. We thank Mohammad-Ali Sepas-Khah
for his advice on statistical analysis.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
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