Table I.
Characteristics of the included studies of topical therapies for early-stage mycosis fungoides
| Author, Year published∗ | Therapy | Cohort description | Treatment regimen | Treatment adverse effects | Outcome(s) of interest |
|---|---|---|---|---|---|
| Ferreira 199019 | Nitrogen mustard | 8 patients; Stage IA = 4, IB = 2, IIA = 2 | Mechlorethamine applied to the entire skin surface, with the exception of the folds. Patients completed 18 cycles, with a median duration of 0.9 months of treatment per cycle | Contact dermatitis, hyperpigmentation | Good response (most lesions completely remitted) in Stage IA: 75%; Stage IB: 50%, Stage IIA: 100% |
| Foulc 200220 | Nitrogen mustard | 22 patients with Stage I | Mechlorethamine 0.2% diluted in 10 mL of solvent and 50 mL of water applied to lesions or the entire skin surface for 1 hour, then washed off with water | Allergic contact dermatitis, irritant contact dermatitis, mild pruritus, pigmentation, xerosis | CR = 59% with a mean treatment duration of 11.7 months |
| Hamminga 198221 | Nitrogen mustard | 17 patients; Stage IA = 8, IB = 6, IIA = 3 | mechlorethamine hydrochloride 10 mg in 40 mL tap water solution applied daily over the entire skin surface | Hyperpigmentation, irritant dermatitis, dry skin, pruritus, urticaria, telangiectasia, allergic contact dermatitis | CR = 82% in early-stage disease with 41-month median follow-up |
| Kim 200322,∗ | Nitrogen mustard | 195 patients; T1 = 107, T2 = 88 | 10 to 20 mg/100 mL solution applied to the entire skin surface daily until complete clinical clearance. Treatment was continued for 6-24 months as maintenance therapy | Irritant or allergic contact reactions, secondary cutaneous malignancies | T1 CR = 65% at median follow-up 73 months, range 5-269 months; T2 CR = 34% at median follow-up 55 months, range 5-242 months |
| Lamberg 198623,∗ | Nitrogen mustard | 88 patients; T1 = 41, T2 = 47 | mechlorethamine 10 mg daily applied to the entire skin surface; tapered frequency if the disease subsided | Not reported | T1 CR = 70% after mean 21 months; T2 CR = 60% after mean 33 months |
| Lessin 201324 | Nitrogen mustard | 260 total (130 in each group) patients with Stage IA, IB, or IIA | Mechlorethamine 0.02% gel or mechlorethamine 0.02% compounded in Aquaphor applied to all affected areas or total skin surface depending on T classification, once daily for 12 months | Skin irritation (18% patients using ointment, 20% gel); pruritus (20%, 25% gel); erythema (18%, 22% gel); contact dermatitis; (19% gel and ointment); skin hyperpigmentation (9%, 7% gel); folliculitis (5%, 7% gel) | CR of intention-to-treat population = 14% for gel and 12% CR for ointment; CR of the efficacy evaluable population = 19% for gel and 15% CR for ointment at mean 5.8 months; response rates gel 58.5% vs ointment 47.7% by CAILS; response rates gel 46.9% vs ointment 46.2% by mSWAT |
| Lindahl 201325 | Nitrogen mustard | 92 patients; T1 = 14 (includes 1 Stage IVA patient), T2 = 78 (includes 2 Stage IVA patients) | mechlorethamine hydrochloride 20 mg dissolved in 40 mL water applied with gauze to lesions or the entire skin surface daily for induction therapy for 14 days. Maintenance therapy of 2 treatments weekly for the first to second month until clearance or discontinued for side effects or progressive disease | Contact dermatitis, secondary cutaneous malignancies | T1 CR = 79%; T2 CR = 51% after median duration of treatment of 16.4 months |
| Ramsay 198826,∗ | Nitrogen mustard | 107 patients; Stage I = 63, Stage II = 44 (different staging system) | mechlorethamine 10 mg in 60 mL of tap water applied daily to the entire skin surface until complete remission. Thereafter tapered every 6 months to every other day application, twice weekly, weekly for 6 months, to stop | Not reported | Stage I CR = 59% after 12.2 months of treatment, 76% after 24 months of treatment; Stage II CR = 41% after 12.2 months of treatment, 45% after 24 months of treatment |
| Stone 200127 | Nitrogen mustard | 6 patients; Stage IA = 1, IB = 5 | Topical nitrogen mustard daily to the entire skin surface area | Not reported | Slight repigmentation of MF lesions in 66% of patients |
| Thomsen 197928 | Nitrogen mustard | 39 patients with histologically proven skin disease only (stage II) | mechlorethamine 20 mg dissolved in 40 mL water/m2 body surface applied daily to the entire skin surface for 0.5 months then weekly maintenance applications | Contact dermatitis | CR = 49% in early-stage skin-only disease |
| Vonderheid 198929,∗ | Nitrogen mustard | 201 patients; Stage IA = 89, Stage IB = 66, Stage IIA = 46 | mechlorethamine 10- 20 mg dissolved in 40-60 mL water applied daily to the entire skin surface except for the genital skin until a complete response was achieved. Once daily or every other day maintenance application for at least 36.5 months | Allergic contact dermatitis (12 patients); carcinogenicity (RR for SCC 7.8, 31 cases; RR BCC 1.8, 27 cases; colon cancer, Hodgkins disease, leukemia, stomach cancer, melanoma) | Stage IA CR = 80%; Stage IB CR = 68%; Stage IIA CR = 61% for mean duration of 53 months |
| de Quatrebarbes 200530 | Nitrogen mustard and corticosteroids | 64 patients; Stage IA = 33, IB = 26, IIA = 5 | mechlorethamine 0.02% aqueous solution twice weekly applications to the entire skin surface followed by an application of betamethasone cream for a 6-month period | 28% of patients had erythema, severe pruritus, burning sensation, or eczematous reaction after a mean of 3.4 ± 2.7 months | Overall CR for early-stage disease = 58% at mean 3.6 ± 2.5 months; Stage IA CR = 61% at mean 3.3 months; Stage IB CR = 58% at mean 3.8 months; Stage IIA CR = 40% at mean 3.0 months |
| Breneman 200231 | Retinoids (bexarotene) | 67 patients; Stage IA = 41; Stage IB = 20; Stage IIA = 5, Stage IIB = 1 | Bexarotene 0.1% gel applied to skin lesions starting daily and increasing up to 4 times daily or the maximal tolerated dose for a median treatment duration of 10.5 months | Rash in 73% of patients; pruritus in 33% of patients; pain in 24% of patients; headache in 6% of patients; vesiculobullous rash in 6% of patients | CR = 21% with median time to response of 4.7 months; IGA stage IA, IB, IIA: CR 21%, Stage IA, IB, IIA: PR 42% |
| Heald 200332 | Retinoids (bexarotene) | 50 patients; Stage IA = 25; Stage IB = 22; Stage IIA = 2; Stage IIB = 1 | Bexarotene gel 1% to all skin lesions 1-4 time daily for at least 3.7 months | 94% of patients experienced at least 1 treatment-related adverse event including irritant dermatitis; low CD4 counts; high glucose; granulocytopenia | PEC (primary end point classification for the study) as CCR (clinical complete response) = 10 % with median time to response of 4.7 months; BSA involvement median change from 9% at baseline to 4.5% at week 44; Investigator global improvement stage IA, IB, IIA, IIB: CR 2%, Stage IA, IB, IIA, IIB: PR 42%; Quality of life >75% moderately or much improved (5-point scale: much, moderately worse, about the same, moderately, much better by week 16); CAILS for stage IA, IB, IIA: CR 10%, stage IA, IB, IIA PR: 36% |
| Apisarnthanarax 200433 | Retinoids (tazarotene) | 19 patients with early-stage MF | Tazarotene 0.1% gel applied to skin lesions once daily for 5.6 months, could also use low-mid potency topical steroids | Skin irritation; erythema, burning, peeling in 84% of patients; fissuring of palms and soles in 11% of patients; transient nausea in 5% of patients; allergic dermatitis in 5% of patients | (all outcomes compared to baseline) BSA involvement mean change −22%; overall disease severity mean change −34%; pruritus difference −0.12%; plaque elevation difference −0.67%; scaling difference −0.70%; erythema difference −1.03%; lesional area mean change −37% after mean duration of treatment of 4.4 months |
| Besner-Morin 201634 | Retinoids (tazarotene) | 10 patients with stage IA-IIA MF | Tazarotene 0.1% cream applied to lesional skin on alternate days for the first 0.5 months and then increased to once daily application if tolerated for a total of 6 months on treatment | 70% experienced mild treatment-related side effects (pruritus, burning, erythema, desquamation) | CR = 60% with mean time to CR of 3.8 months; IGA stage IA, IB, IIA: CR 60%, Stage IA, IB, IIA: PR 0; AILDS 63% reduction of erythema, 86% reduction of scaling |
| Kartan 201935 | Corticosteroids | 31 patients; Stage IA = 22, IB = 9 | Twice daily application to lesional skin with class 1, 2, or 3 topical steroids including clobetasol propionate 0.05%, triamcinolone 0.1% (2/37, 5%) or mometasone 0.1% (1/37, 3%) ointments alone or in combination with a lower potency topical steroid, either desonide 0.05% or hydrocortisone 2.5% for intertriginous or facial skin | Not reported | Stage IA CR = 18%; Stage IB CR = 22% at median follow-up of 3 months; 65% decrease in BSA, 67% in mSWAT (however, decrease in BSA and mSWAT were for study patients of all stages initially receiving topical steroid monotherapy) |
| Zackheim 199836,∗ | Corticosteroids | 79 patients; Stage T1 = 51, T2 = 28 | Twice daily application to lesional skin with class 1, 2, or 3 topical steroids including 0.05% clobetasol propionate, 0.05% diflorasone diacetate, 0.05% halobetasol propionate, 0.05% fluocinonide, 0.1% triamcinolone acetonide, or 0.05% betamethasone valerate | Temporary minor irritation (2); Atrophy (1); Stretch marks (1); Temporary serum cortisol below the lower limit of normal (T1 = 4 patients, T2 = 6 patients) | Stage T1 CR = 63%; Stage T2 CR = 25% at a median follow-up of 9 months |
| Zackheim 199037,∗ | Carmustine | 109 patients; Stage IA = 49, Stage IB = 38, Stage IIA = 22 | Daily application of 10 mg/day to skin lesions. Most were treated for 1.6-3.3 months with a maximum of 4 months | Cutaneous adverse effects: erythema; telangiectasia; hyperpigmentation. Laboratory abnormalities: mild bone marrow depression; increase in aspartate aminotransferase | Stage IA CR = 86%, Stage IB CR = 47%, Stage IIA CR = 55% with median time to achieve CR of 2.7 months |
| Kannangara 201038 | 5-fluorouracil | 6 patients; Stage IA = 4; stage IB = 1, Stage IIA = 1 | 5-fluorouracil applied daily to skin lesions for 3-18 months | 2 patients experienced treatment-related adverse reactions that were mild and self-limited | CR = 67% for 3-18 months |
| Demierre 200339 | Methotrexate-laurocapram | 10 patients with stage IA or IB MF | Doses of 12.5 or 25 g/m2 applied to the entire skin surface every other day for 6 consecutive months | A total of 10 adverse events were reported in 7/10 patients. Pruritus 60%; rash 20%; dry skin 10%; contact dermatitis 10% | No CRs, slight-to-moderate response in 70% at 6 months |
| Dummer 199340 | Hexadecylphosphocholine | 10 patients; Stage IA = 6; Stage IB = 2; Stage IIA = 2 | Once daily application to a defined area during the first week, followed by twice daily application during the second week. Treated areas ranged between 200 and 3200 cm2 and duration of therapy ranged from 2 to 3 months | Slight erythema, fine scaling, and burning sensation within the first 10 minutes of application | CR = 20% at 2-3 month follow-up |
| Duvic 200141 | Peldesine (BCX-34) | 43 patients; Stage IA = 20; Stage IB = 23 | Twice daily applications to the entire skin surface for up to 6 months; randomized, double-blinded, placebo-controlled study | Pruritus 21%; rash 14% | Clinical CR = 2% at 6 months; overall response at study end not significantly different from placebo (P = .79); BSA involvement mean change 3% improvement (P = .84 compared with placebo) |
| Lebas 201742 | Ingenol mebutate | 9 patients with stage IB MF | 0.05% gel applied to target skin lesions in 2 applications spaced one week apart | All patients experienced treatment-related adverse events (burning sensations, oozing, and crusting) but did not stop treatment. 73% of lesions had mild-to-moderate hyperpigmentation | The mean overall CAILS score was reduced by 58.2%. The mean scores were improved by 73.6% for erythema, 93.9% for scaling, and 97.9% for plaque elevation at 2 month follow-up |
| Lebas 202043 | Topical methotrexate with topical drug carrier OFA-LP3 | 10 patients with stage IB MF | Four weekly treatments of OFA-LP3 (a proprietary microemulsion of oil-in-water with surface tension-breaking adjuvants carrying 3% methotrexate) on selected areas | Not reported | Mean modified CAILS scores were improved by 51.3% ± 33.6% for erythema, 53.2% ± 29.8% for scale, 49.6% ± 41.7% for plaque elevation, and 51.3% ± 32.2% for the total score at 2 month follow-up |
| Rook 201544 | Resiquimod | 12 patients; Stage IA = 1; Stage IB = 10; Stage IIA = 1 | Resiquimod 0.06% or 0.03% applied initially 3 or 5 times (respectively) weekly for 2 months, followed by 1 month rest, then another 2 months of treatment, followed by another month rest period | Skin irritation in 25% of patients; skin erosion in 33%; fever in 17%; headaches in 17%; myalgia in 8% of patients | CR = 17% at 6 months; CAILS score CR 33%, PR 42%; SWAT (evaluate overall disease burden & response = the overall CR) CR 17%, PR 75% |
AILDS, Assessment of Index Lesion Severity; BCC, basal cell carcinoma; BSA, body surface area; CAILS, composite assessment of index lesion severity; CCR, clinical complete response; CR, complete remission 100% clearance of disease (or as defined by each individual study); IGA, investigator global assessment; MF, mycosis fungoides; mSWAT, Modified Severity-Weighted Assessment Tool; OFA-LP3, oxygen flow-assisted LP3 carrier; PEC, primary end point classification for the study; PR, partial remission; RR, relative risk; SCC, squamous cell carcinoma; Stage IA, limited skin involvement (T1, N0, M0, B0 or B1); Stage IB, skin-only disease (T2, N0, M0, B0 or B1); Stage IIA, T1-2, N1-2, M0, B0 or B1; T1 Stage, patch/plaque disease <10% of the skin surface; T2 Stage, patch/plaque disease 10% or more of the skin surface.
∗
When there were multiple studies on the same cohort, only the most recent study with information on our primary outcomes was cited.