In the management of the patient with mycosis fungoides (also called CTCL), the dermatologist should be expected to manage 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 a specialized medical center or the local oncologist may be indicated. Nonetheless, most dermatologists feel comfortable with directing light therapy, especially if their practice contains a phototherapy unit. Therefore, the following successful therapeutic modalities will be briefly discussed: topical steroid, bexarotene gel, nitrogen mustard ointment, phototherapy, bexarotene oral capsules, interferonalpha (INF-α) injections, methotrexate, and vorinostat. This includes how to initiate the therapy, expected response rates, possible acute side effects, how to manage maintenance therapy, including long term side effects, and how long to give any particular therapy a trial before moving on due to unresponsiveness. For a more complete discussion, please refer to Heald et al.1
I often use high-potency topical steroids as adjunctive therapy in MF, owing to their antiinflammatory and lymphocytic pro-apoptotic characteristics. I consider it palliative as monotherapy due to the short times before recurrence of disease upon discontinuation. However, complete responses to clobetasol applied twice daily for two to three months were seen in 63 percent of limited early-stage disease in one study.2 Aggressively use class I steroid on any suspicious eruption that could represent early relapse, including contact dermatitis or even insect bites, because this may help maintain remission and differentiate between benign dermatitides and malignant disease. Should any lesions persist for more than four to six weeks in this scenario, I recommend histological evaluation to verify disease presence.
It is best to reserve Bexarotene 1% gel (Targretin, Eisai) for treatment of <15 percent body surface area due to its ability to cause retinoid-induced irritant dermatitis. I instruct patients 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-aday application is best because there is dose responsiveness to the medication. Manage the irritant response by either decreasing the frequency of application or, better still, by adding daily applications of topical corticosteroid. Once the course has been completed, I ask the patient to hold the bexarotene for one month to allow for the retinoid dermatitis to resolve and then reassess for disease burden (one cycle = four months total). Consider another cycle of therapy if objective but incomplete response is obtained. As a retinoid, there is no known cumulative toxicity with regard to cutaneous carcinogenesis or structural damage. In fact, the retinoids typically have activities that counter these effects found in other MF therapies, such as light therapy. The drug is not absorbed to any significant degree, so no blood monitoring is required.
Topical alkylating agents are available in two varieties for MF treatment: mechlorethamine (nitrogen mustard) (Mustargen, Lundbeck) and bischloroethyl 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 to cause post-inflammatory hyperpigmentation, erythema, telangectasias, skin tenderness, and burning sensations apart from the contact hypersensitivity reactions. Patients self direct topical applications of 10mg% or 20mg% mechlorethamine ointment applied from chin to toes, with sparing application in intertriginous folds, once daily in the induction phase. This is performed for up to three or four months to adequately assess for response. Expect a 60–90 percent complete remission rate with this therapy on earlystage disease.3 Once remission is obtained, I recommend a maintenance regimen, 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. I also use mechlorethamine applications 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 preexisting photodamage.
Twenty or 40mg% BCNU ointment is applied topically as spot treatment for less than 15 percent body surface area at a time. As with mechlorethamine, this should be performed for three to four months to adequately assess for response. Expect a 60–85 percent complete response rate with this therapy on early stage disease.4 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 the medication leading to bone marrow suppression (thrombocytopenia and lymphopenia). Therefore, obtain blood counts every other week while on therapy and for one month post-therapy. The risk seems greatest if daily application exceeds 25mg.5 Secondary cutaneous malignancies have not been reported with BCNU.
Phototherapy may be delivered as broad-band ultraviolet B (BB-UVB), narrowband ultraviolet B (NB-UVB), ultraviolet A (UVA), or photochemotherapy using psoralen and UVA (PUVA). These therapies are dose-responsive, and most regimens use at least three-times-a-week dosing in the induction phase. The initial dose is limited by Fitzpatrick skin type, but the dose is incrementally increased as therapy continues. For a detailed discussion of how to deliverdeliver phototherapy safely and effectively, refer to the work by Zanolli and Feldman.6 In general, at least 20–30 doses need to be delivered before being able to adequately assess for efficacy. If a response is obtained, continue dosing until complete clearance is obtained (usually 50–60 treatments). Expect to reliably obtain remission of early-stage disease with PUVA therapy.7,8 If a complete response is not obtained, add an adjuvant therapy with oral retinoid (such as bexarotene) or subcutaneous INF injections. Once remission is obtained, slowly taper dose frequency to the most infrequent that maintains longterm remission (the maintenance phase). 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, consider discontinuing the therapy altogether.
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, since they can avoid both an oral pill and any travel to the light unit, particularly if they live more than half an hour from a phototherapy center. Unfortunately, light therapy has cumulative risks for non-melanoma and melanoma skin cancers. The total number of UVA treatments should not exceed 250 over a lifetime, except in special circumstances, in order 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, I consider PUVA more efficacious, especially for plaque-stage disease. Sites of sanctuary from light often occur in intertriginous zones, in skin folds, and on the eyelids. I use adjunctive therapy with localized bexarotene gel, BCNU, imiquimod 5% cream, or radiation therapy in order to achieving complete remission in these instances.
Bexarotene (Targretin, Eisai) oral therapy is available in 75mg tablets and should be 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. Take care in considering this therapy if the patient is already at risk to develop these side effects, such as in severe coronary artery disease, uncontrolled diabetes or other poorly controlled metabolic syndrome. Other side effects may include headache, hepatitis, pancreatitis (from uncontrolled hyperlipidemia), neutropenia, and thrombocytopenia. Often dose reduction is necessary to avoid these effects but is to be discouraged if possible as MF is doseresponsive to this medication. Expected response rates range from 30 to 60 percent depending on disease stage and should be seen within 12 weeks of instituting therapy. This therapy is considered palliative, as disease rapidly returns when the medication is discontinued, and median response times are about 18 months before relapse.9,10 In combination with INF and/or phototherapy, it can be a component of a remittive regimen.11,12 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, I recommend the following:
- 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 co-morbid 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.
- If the lipid panel is normal, start a fibric acid derivative, fenofibrate (Tricor, Abbott) 200mg daily, for one week prior to instituting bexarotene capsules. Gemfibrozil (Lopid, Pfizer) is contraindicated as it increases serum bexarotene levels.
- If the lipid panel is abnormal, start the HMG Co-A reductase inhibitor atorvastatin (Lipitor, Pfizer) 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.
- Optimize thyroid function with levothyroxine for at least one week prior to instituting bexarotene capsules.
- Monitor with a fasting lipid panel, liver function test (CPK if needed), T4, and CBC every two weeks until on a stable dose with no further concomitant medication changes required. Note that the 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, Roche; Intron-A, Schering- Plough) is self-administered by the patient as a subcutaneous injection of three to 18 million units three times per week. Start with three million units per dose for three months and if there is minimal or no response, the dose may be increased by three million units every six to 12 weeks as tolerated. When the patient clears or is at maximal response, maintain the dose for three additional months and then slowly taper over 12 months, either by frequency of administration or by dose. Expect partial response rates ranging from 30 to 75 percent; complete responses are rare.13,14 Acute side effects include flulike symptoms of malaise, myalgia, headache, and fever. Bedtime dosing and pretreatment with acetaminophen help reduce these side effects, but most patients note diminishment of these symptoms after four to six weeks of therapy. Unfortunately, chronic toxicities include neuropathy, depression, chronic fatigue, and hypothyroidism. Side effects are doserelated and reversible. Perform a CBC, AST, ALT, TSH and urinalysis once every two weeks for six to 12 weeks at the start or with dose increases and then periodically thereafter looking for leukopenia, thrombocytopenia, anemia, proteinuria, transaminitis, and hypothyroidism.
Many dermatologists are comfortable with methotrexate because of its frequent use in management of severe psoriasis. Methotrexate is delivered either orally or subcutaneously in doses ranging from 5 to 50mg once weekly. Patients with early-stage MF can be expected to have overall response rates of 33 percent that should occur within six to 12 weeks of instituting therapy.15 Toxicities include nausea, gastritis, leukopenia, hepatitis, mucositis, and pneumonitis. Therefore, perform a baseline CBC, urinalysis, basic metabolic profile, liver panel, and viral hepatitis screening. A frank discussion regarding avoidance of pregnancy, alcohol, sulfa-based antibiotic and chronic nonsteroidal anti-inflammatory drug use is warranted. I suggest monitoring with 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 should ensue.
Vorinostat affects gene expression by inhibiting histone deacetylase, but how this mechanism translates into clinical efficacy in MF is still largely unknown. Administer it as monotherapy at 400mg per day. I will try a dose reduction to 300mg a day if it is poorly tolerated, but efficacy decreases at lower doses. Partial response rates in the pivotal trial were around 30 percent, with palliation of pruritus as a notable aspect of vorinostat therapy. The most common side effects include thrombocytopenia, dehydration, and diarrhea; I therefore monitor CBC and CMP, push oral fluids, and use loperamide symptomatically. The median time to response is 12 weeks, but improvement may continue to peak up to over 12 months.16
A Role for Dermatologists
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 primarily cutaneous diseases, the dermatologist
remains best suited not only to guide treatment
decisions, but also to perform long-term follow-
up for patients with MF.
Dr. Mark is an investigator on clinical trials with Eli Lilly and Novartis.
This article is part three of a three-part series. To access Parts One and Two, visit PracticalDermatology.com.
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