Mycosis Fungoides.pdf
description
Transcript of Mycosis Fungoides.pdf
a report by
Lawrence A Mark , MD , PhD , FAAD
Assistant Professor of Dermatology, Indiana University School of Medicine, and Service Chief, Dermatology, Wishard Hospital
Successful Treatment of Mycosis Fungoides
Primary cutaneous T-cell lymphoma is a heterogenous group of non-
Hogkin’s lymphomas—including mycosis fungoides (MF), anaplastic large cell
lymphoma, adult T-cell lymphoma/leukemia, subcutaneous panniculitis-like
T-cell lymphoma, and extranodal natural killer (NK)/T-cell lymphoma, nasal
type—each uniquely distinguishable based on clinical presentation,
immunohistochemistry, prognosis, and treatment strategies. The classification
schema is constantly being revised to accommodate new information as it is
gathered on this rare set of diseases; however, it is widely recognized that MF
is by far the most prevalent of this group, accounting for approximately 50%
of primary cutaneous T-cell lymphomas1 with an incidence of 0.64/100,000
person-years.2 This incidence has been on the rise over the last 30 years,
although it is not clear whether this is due to better diagnostic tools (such as
polymerase chain reaction [PCR]-based T-cell gene rearrangement
technology), heightened awareness among clinicians, or a true rise secondary
to an as yet unidentified environmental factor or infectious agent.
Nonetheless, it has become a more prominent disease, posing difficult
management choices for the clinician, but also drawing clinical research to
help tackle this difficulty. New treatment choices are now available that were
unheard of 10–20 years ago, such as retinoid therapy with bexarotene,
histone deacetylase therapy with vorinostat, and monoclonal antibody
therapy with alemtuzumab and denileukin diftitox. In this article, I would like
to first discuss tenets of therapy in general, but then focus on the treatment
options readily manageable by the dermatologist specifically.
Tenets of Therapy
Clinically Visible Disease Should Be Actively Treated
Once the diagnosis of MF has been established, one must determine what the
goal of therapy will be: palliation or remission. As MF usually occurs in an
aging population that may have numerous other comorbidities leading to
limited life expectancy, palliative interventions may be considered for these
individuals to avoid unnecessary side effects of more aggressive therapy. A
frank and honest discussion with the patient and family regarding the typical
indolence of MF and the place of various therapies in this disease will help
guide the decision.
However, for younger patients or those in general good health, an attempt
at achieving remission or near complete remission is recommended. This is
because without treatment it is expected that the disease will continue to
progress, however slowly or quickly, from the patch stage to involve more
skin area, become plaque stage, form tumors, and then involve lymph
nodes and/or blood. The exception to this may be Woringer-Kollop disease
or pagetoid reticulosis subsets of MF, which by definition are non-
progressive and isolated in skin involvement. As indirect evidence for the
assertion that MF will progress if untreated, one may scrutinize a seminal
article from Stanford University reporting the prognoses for the various
stages of MF. Their data show that only stage IA disease is associated with
no measurable decrease in life expectancy, possibly because all of their
patients obtained treatment, even those with early-stage disease in whom
treatment may be able to eliminate tumor burden.3 This agrees with the
findings of Swanbeck et al., who compared mortality of MF in the pre- and
post-psoralen with ultraviolet A therapy (PUVA) eras, a therapy generally
considered useful only in stage IA–IIA disease, revealing an overall 50%
reduction in death rate.4 The logical conclusion is to actively treat clinically
identifiable disease when able, thereby halting progression through
decreased tumor burden and avoiding increased mortality. Additionally,
early-stage disease is more amenable to obtaining sustainable complete
remission, whereas this is usually unrealistic in more advanced stages of MF.
However, one must remain cognizant that maintenance of remission may
require long-term ongoing treatment regimens, which may have cumulative
adverse effects in themselves. A frank discussion of risk versus benefit is
always required before embarking on long-term therapy for these patients.
Specific Therapy Is Based on Stage of Disease
Just as the astute oncologist would avoid multi-agent chemotherapy for MF
with only a few patches of involvement, so the astute dermatologist would
not treat progressive tumor-stage disease with topical nitrogen mustard
alone. However, most patients do present with early disease that is
amenable to skin-directed therapies that the dermatologist will be able to
manage. Table 1 addresses which first-line therapies may be best suited for
any particular disease stage and generally expected responses. Obviously,
clinician-specific preferences, medication side-effect profiles, patient
comorbidities, and disease aggressiveness exhibited by clinical behavior
often color the specific choice of therapy. This list is not intended to be
comprehensive, nor an edict for correct choices of therapy for any one
individual, but merely a guideline to aid clinical practice.
Skin Cancers
69© T O U C H B R I E F I N G S 2 0 0 8
Lawrence A Mark, MD, PhD, FAAD, is an Assistant Professorof Dermatology at the Indiana University School of Medicinein Indianapolis and Service Chief for Dermatology at the local county-funded hospital, Wishard Hospital, and thedermatological arm of the Mel and Bren Simon CancerCenter’s Multidisciplinary Melanoma Clinic. Dr Mark’sresearch interests are in cutaneous T-cell lymphomas andmelanoma. He is a Fellow of the American Academy ofDermatology (AAD) and a member of both the Society for
Investigative Dermatology (SID) and the Biophysical Society. Dr Mark received his MD, PhD,and residency training at Indiana University School of Medicine.
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Patients in Remission Should Be Followed Up Indefinitely
Certainly, those patients with only partial response or palliation require
continued follow-up to periodically assess for disease progression. Such
progression would weigh heavily on further therapeutic choices and expected
prognosis. However, if complete remission has been achieved, what guidelines
are there for continued follow-up? This author is currently unaware of any
specific evidence-based recommendations such as there are for melanoma or
squamous cell carcinoma. While patients are on maintenance therapy for their
remission, they are usually seen at least three to four times per year, allowing
for relatively close monitoring. What if the patient remains in remission, even
after complete cessation of all therapeutic modalities? My practice is to at least
see these individuals every three to four months for two years, followed by
once every six months for three years and then yearly thereafter, with
instructions to return more urgently if they have concern for recurrence.
Typically, they have high-potency topical steroids on hand, and should raise
concern if there is a ‘rash’ that persists despite four to six weeks of medication
applications. For practical purposes, the definition of ‘cure’ as being free of
disease for eight years after all therapy has ended worked in a nitrogen
mustard trial5 and has been suggested by Peter Heald as a standardizable
definition to uphold.6 Again, without evidence-based medicine to guide, other
than standard of care for non-Hogkins lymphomas as described by the National
Comprehensive Cancer Network (NCCN) guidelines,7 I see these individuals
once yearly indefinitely.
Particular therapies that the dermatologist should be expected to manage are
any skin-applied, skin-directed, or oral therapies available for this disease.
When special equipment is needed (such as for light therapy, total skin electron
beam, and extracorporeal photopheresis) or infusional therapies are required,
referral to the oncologist or specialized medical center may be indicated.
Nonetheless, most dermatologists feel comfortable with directing light therapy,
especially if their practice maintains the light box. Therefore, the following
successful therapeutic modalities will be briefly discussed: topical steroid,
bexarotene gel, nitrogen mustard ointment, phototherapy, bexarotene oral
capsules, interferon alfa (INF-α) injections, methotrexate, and vorinostat. For a
more complete discussion, please refer to Heald et al.8
High-potency topical steroids are typically used as adjunctive therapies
in MF owing to their anti-inflammatory and lymphocytic pro-apoptotic
characteristics. It is considered palliative as monotherapy due to the short times
before recurrence of disease on discontinuation. However, complete responses
to clobetasol applied twice daily for two to three months were seen in 63% of
limited early-stage disease.9 Aggressive use of a class I steroid on any suspicious
eruption that could represent early relapse, including contact dermatitis and
insect bites, may help maintain remission and differentiate between benign
dermatitis and malignant disease. Should lesions persist for more than four to
six weeks in this scenario, histological evaluation is recommended.
Bexarotene 1% gel (Targretin®) is typically used for <15% body surface area
due to its ability to cause retinoid-induced irritant dermatitis.10 Patients are
instructed to begin applying the medication once nightly for one week,
followed by twice daily for one week, and then finally thrice daily thereafter for
a total of three months. If tolerated, four-times-a-day application is best as
there is dose responsiveness to the medication. Irritant response is managed by
either decreasing the frequency of application or, better still, by adding daily
applications of topical corticosteroid. Once the course has been completed, the
patient is allowed to rest for one month to allow for the retinoid dermatitis to
Skin Cancers
70 U S D E R M A T O L O G Y
Table 1: Suggested First-line Therapies Matched to Disease Stage
Stage Modality Response TypeI. Limited patches to generalized plaques Topical steroid Palliative, maintenance for non-descript lesions
Bexarotene gel Remittive or palliative
Nitrogen mustard ointment Remittive (includes mechlorethamine and bis-chlorethyl nitrosourea)
Spot radiation Remittive
Phototherapy Remittive
II. Generalized plaques or tumors with dermatopathic nodes Nitrogen mustard ointment Remittive
Phototherapy Remittive
Total skin electron beam Remittive, requires encore maintenance therapy
Bexarotene oral Palliative, remittive in conjunction with phototherapy
Interferon alfa Palliative, remittive in conjunction with phototherapy
Denileukin diftitox Palliative
Gemcitabine Palliative
III. Erythroderma Extracorporeal photopheresis Palliative
Total skin electron beam Remittive, requires encore maintenance therapy
Bexarotene oral Palliative
Denileukin diftitox Palliative
IV. Nodal or visceral involvement Bexarotene oral Palliative
Denileukin diftitox Palliative
Alemtuzumab Remittive
Traditional single-agent chemotherapy Methotrexate, gemcitabine, chlorambucil, cyclophosphamide, etoposide,
liposomal doxarubacin; all considered palliative with rare remission
Relapsed/unresponsive disease Alternate agent in stage-specific list As above
Vorinostat Palliative
Traditional single-agent chemotherapy Methotrexate, gemcitabine, chlorambucil, cyclophosphamide, etoposide,
liposomal doxarubacin; all considered palliative with rare remission
Allogeneic stem-cell transplantation Remittive
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resolve and then reassessed for disease burden (cycle 1). If objective response
is obtained, another cycle of therapy may be considered. As a retinoid, there
should be no cumulative toxicity with regard to cutaneous carcinogenesis or
structural damage. In fact, the retinoids typically have activities that counter
mutagenic effects. The drug is not absorbed to any significant level, so no
blood monitoring is required.
Topical alkylating agents are available in two varieties for MF treatment:
mechlorethamine (nitrogen mustard) (Mustargen®) and bis-chloroethyl
nitrosourea (BCNU) (BiCNU, Carmustine®). Both are best when compounded
into ointment form for delivery because the solution forms are more prone to
allow development of contact sensitization, the alcohol in the vehicle has no
emollient property, and the product is labile in solution at room temperature.
Each compound has a similar risk of causing post-inflammatory hyper-
pigmentation, erythema, telangectasias, skin tenderness, and burning
sensations apart from the contact hypersensitivity reactions.
Ten or 20mg% mechlorethamine ointment is applied topically from chin to
toes, with sparing application for intertriginous folds once daily in the induction
phase. This is performed for up to three or four months to adequately assess
for response. One should expect a 60–90% complete remission rate with this
therapy on early-stage disease.5,11 Once remission is obtained, a maintenance
regimen is recommended, but no specific regimen has been studied. One
recommendation could be to taper application frequency over several weeks
down to at least once weekly, as long as no recurrence is found.
Mechlorethamine applications are often used as an encore to maintain
remission after radiotherapy. Unfortunately, non-melanoma skin cancer is a
known long-term side effect of chronic application, even in the absence of
pre-existing photodamage.12,13 Twenty or 40mg% BCNU ointment is applied
topically as spot treatment for less than 15% body surface area at a time. This
is performed for three to four months to adequately assess for response. One
should expect a 60–85% complete response rate with this therapy on early-
stage disease.14 Maintenance regimens have not been studied and most
practitioners repeat cycles of treatment as needed. Only a limited skin area can
be treated at any one time due to percutaneous absorption of BCNU leading
to bone marrow suppression (thrombocytopenia and lymphopenia). Therefore,
it is recommended that blood counts be obtained every other week while on
therapy and for one month post-therapy. The risk seems greatest if daily
application exceeds 25mg.15 Secondary cutaneous malignancies have not been
reported with BCNU.
Phototherapy may be delivered as broad-band ultraviolet B (BB-UVB),
narrow- band ultraviolet B (NB-UVB), ultraviolet A (UVA), or
photochemotherapy using PUVA. There is dose responsiveness to the
therapy and most regimens use at least three-times-a-week dosing in the
induction phase. Initial dose is limited by Fitzpatrick skin type, but
incremental dose increases are given as therapy continues. For a detailed
discussion of how to deliver phototherapy safely and effectively, refer to the
work by Zanolli and Feldman.16 In general, at least 20–30 doses need to be
delivered before being able to adequately assess for efficacy. If a response is
obtained, dosing is continued until complete clearance is obtained (usually
50–60 treatments). Expect to reliably obtain remission of early-stage disease
with PUVA therapy.17,18 If complete response is not obtained, the addition of
adjuvant therapy with an oral retinoid (such as bexarotene) or subcutaneous
INF injections can be quite efficacious. Once remission is obtained, the
maintenance phase is obtained by slowly tapering dose frequency to the
most infrequent that maintains long-term remission. This ends up being
about once every other week for UVB and as little as once a month for
PUVA. If remission has been retained for five years, cessation of therapy may
be considered.
UVB phototherapy is best suited for patients with thin lesions (patches), owing
to the fact that UVB penetrates much less deeply than UVA wavelengths.
However, home phototherapy with UVB appeals to many patients due to not
having to take an oral pill and convenience, particularly if they live more than
half an hour from a phototherapy center. Light therapy has cumulative risks for
non-melanoma and melanoma skin cancers. It is recommended that the total
number of UVA treatments not exceed 250 over a lifetime to reduce this risk.
Other risks include photosensitivity, phototoxicity, cataract formation, and
hyperpigmentation. Furthermore, psoralen exacerbates the risk for
phototoxicity and adds a risk for nausea and vomiting, particularly if doses
greater than 30 or 40mg per session are used. Nonetheless, PUVA is considered
more efficacious, especially for plaque-stage disease.19,20 Sites of sanctuary from
light often occur in intertriginous zones, in skin folds, and on the eyelids.
Adjunctive therapy with localized bexarotene gel, BCNU, imiquimod 5%
cream, or radiation therapy can be effective for achieving complete remission.
Bexarotene (Targretin®) oral therapy is available in 75mg tablets and initially
dosed at 300mg/m2/day. It is generally well tolerated but does lead to central
hypothyroidism, hypercholesterolemia, and hyperlipidemia that must be
monitored and controlled with concomitant medications. Other side effects
may include headache, hepatitis, pancreatitis (with uncontrolled
hyperlipidemia), neutropenia, and thrombocytopenia. Often dose reduction is
necessary to avoid these effects, but is to be discouraged if possible as MF is
dose-responsive to this medication. Expectations are for response rates ranging
from 30 to 60% depending on disease stage. This therapy is considered
palliative as disease rapidly returns when the medication is discontinued and
median response times are about 18 months before relapse.21,22 In combination
with INF and/or phototherapy, it can be a component of a remittive
regimen.23,24 Combination therapy is advantageous in that bexarotene may be
used at lower doses, reducing the risk for systemic toxicity.
In order to safely and effectively deliver the medication, the following
recommendations have been proposed:
• Before starting a patient on oral bexarotene, obtain a baseline fasting lipid
panel, liver function test, thyroid-stimulating hormone (TSH), free thyroxine
(T4), pregnancy test, and complete blood count (CBC). Screen for comorbid
conditions that may interfere with therapy (obesity, diabetes, alcoholism,
and estrogen and thiazide use). Provide information on diet and exercise.
Pregnancy is an absolute contraindication to therapy with bexarotene.
• Start a fibric acid derivative, fenofibrate (Tricor®) 200mg daily, for one week
prior to instituting bexarotene capsules. Gemfibrozil (Lopid®) is not
recommended as it increases bexarotene levels.
• If the lipid panel is abnormal, start an HMG Co-A reductase inhibitor,
atorvastatin (Lipitor®) 20mg once daily for one week, prior to instituting
bexarotene capsules. Be aware that combination therapy with fenofibrate
and atorvastatin increases the risk for rhabdomyolysis, myopathy, and acute
renal failure; therefore, additional monitoring of creatine kinase (CPK) and
symptoms is required.
Successful Treatment of Mycosis Fungoides
71U S D E R M A T O L O G Y
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• Optimize thyroid function with levothyroxine for at least one week prior
to instituting bexarotene capsules.
• Monitor fasting lipid panel, liver function test, CPK (if needed), T4, and a
CBC every two weeks until on a stable dose with no further concomitant
medication changes required. Note that TSH need not be further tested as
this will reliably go to zero on bexarotene oral therapy. Once stable,
monitoring labs may be reduced to once every three months.
INF-α (Roferon-A®, Intron-A®) is self-administered by the patient as a
subcutaneous injection of three to 18 million units three times per week.
Starting with three million units per dose for three months is
recommended, and if there is minimal or no response, the dose may be
increased as tolerated. When the patient clears or is at maximal response,
the dose should be maintained for three additional months and then
slowly tapered over 12 months either by frequency of administration or
by dose. Expected partial response varies from 30 to 75%, but there is
rarely a complete response.25–28 Acute side effects include flu-like
symptoms of malaise, myalgia, headache, and fever. Bedtime dosing and
pre-treatment with acetaminophen help reduce these side effects, but
most patients note diminishment of these symptoms after four to six
weeks of therapy. Unfortunately, chronic toxicity includes neuropathy,
depression, chronic fatigue, and hypothyroidism. Side effects are dose-
related and reversible. Laboratory studies should be directed at
monitoring for abnormalities of leukopenia, thrombocytopenia, anemia,
proteinuria, transaminitis, and hypothyroidism.
Methotrexate is delivered either orally or subcutaneously in doses ranging from
5 to 50mg once weekly. Patients with early-stage disease can be expected to
have overall response rates of 33% and should occur within six to 12 weeks of
instituting therapy.29 Toxicities include nausea, gastritis, leukopenia, hepatitis,
mucositis, and pneumonitis. Therefore, baseline CBC, urinalysis, basic
metabolic profile, liver panel, and viral hepatitis screening is recommended. A
frank discussion regarding avoidance of pregnancy, alcohol, sulfa-based
antibiotic and chronic non-steroidal anti-inflammatory drugs use is warranted.
Suggested monitoring includes CBC and liver function tests at one, two, and
four weeks after initiation of therapy. If no abnormalities occur, less frequent
monitoring of at least once every three months is recommended.
Vorinostat affects gene expression by inhibiting histone deacetylase, but how
this mechanism translates into clinical efficacy in MF is still largely unknown. It
is administered as monotherapy at 400mg per day with decreased efficacy at
lower doses. Partial response rates in the pivotal trial were around 30%, with
palliation of pruritus as a notable aspect of vorinostat therapy. The most
common side effects include thrombocytopenia, dehydration, and diarrhea;
therefore, blood monitoring, pushing oral fluids, and symptomatic use of
loperamide are required. The median time to response is 12 weeks.30
In summary, there is an exciting list of therapies, some old and some new, with
which the dermatologist can readily treat their MF patients. Expect more oral
formulations to be on the way in the near future, as this appears to be where
the greatest thrust of current pharmaceutical research lies. Although the array
of choices may seem daunting at first, once the goal of therapy has been
defined—remission or palliation—the choices become clearer. Additionally,
limiting therapeutic choices to those appropriate for the patient’s current stage
of disease eases the decision-making process. With common sense and
knowledge of the therapy being administered, the dermatologist can
effectively and safely treat their ward. As with other cutaneous malignancies,
the dermatologist is best suited not only to treat, but also to perform long-term
follow-up, once the patient is in remission. ■
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72 U S D E R M A T O L O G Y
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