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Efficacy of treatments for mycosis fungoides and Sézary syndrome: Nationwide survey responses

  • Author(s): Gettler, Samuel L
  • Fung, Maxwell A
  • et al.
Main Content

Efficacy of treatments for mycosis fungoides and Sézary syndrome: Nationwide survey responses
Samuel L Gettler MD1 and Maxwell A Fung MD2
Dermatology Online Journal 11 (3): 6

1. Department of Dermatology, New York Medical College, Valhalla, NY
2. Department of Dermatology, University of California Davis. maxwell.fung@ucdmc.ucdavis.edu


Abstract

Background: Numerous treatments have been used to treat the mycosis fungoides (MF) and Sézary syndrome (SS) variants of cutaneous T-cell lymphoma (CTCL). The relative efficacy of different treatments is largely unknown. Objective: To determine the frequency of therapies ranked most effective and least effective for treatment of MF and SS in a sampling of dermatologists in the United States. Methods: Fellow members in the American Academy of Dermatology in the United States between the ages of 35 and 65 years were surveyed regarding demographic variables and treatment efficacy for patch/plaque MF (stages Ia-Ib CTCL), tumor stage MF (stage IIb), and erythrodermic MF/SS (stage III). Results: Based on 1,399 responses, PUVA was preferred for the management of patch/plaque MF. Total skin electron beam (TSEB) therapy was preferred for tumor stage MF. Photopheresis (extracorporeal photochemotherapy) was preferred for erythrodermic MF/SS, followed closely by TSEB. Especially for tumor stage and erythrodermic MF/SS, physicians without a clear preference comprised the largest group. No significant variation depending on practice type, degree of practitioner experience, or geographic location was identified. Conclusion: PUVA was the preferred treatment for Stage Ia and Ib MF. The predominance of surveys with indeterminate responses suggests limited experience and in the treatment of CTCL, especially in advanced stages.



Introduction

Therapy for mycosis fungoides (MF) and Sézary syndrome (SS) is largely based on clinical stage (See Tables 1 and 2)[1]. Although treatment for early or localized patch stage MF may occasionally appear to result in cure [2], the practical aim of therapy in general is to achieve and maintain clinical remission, to decrease morbidity, and to palliate advanced disease. Multiple therapeutic modalities exist, ranging from topical therapy, phototherapy, photopheresis (extracorporeal photochemotherapy), radiation therapy, immunotherapy, chemotherapy, or newer agents such as anti-tumor vaccines [3] and antibody fusion toxins [4]. Commonly used topical agents include high-potency topical corticosteroids [5], carmustine (BCNU) [6, 7], and mechlorethamine (nitrogen mustard) [8]. Phototherapy may consist of psoralen with ultraviolet A photochemotherapy (PUVA) [9], ultraviolet-B (UVB) broadband (280-320 nm) [10], and more recently narrowband (TL-01-311 nm) UVB [11, 12], and others [13, 14]. Electron beam radiation has been used locally and for total body irradiation [15]. Systemic agents include interferons (mostly α-interferon) [16], retinoids [17, 18], methotrexate [19], and other agents [20]. Photopheresis has been employed against erythrodermic MF or Sézary syndrome. The above treatments can be used as monotherapy and some treatments have been used together in combination or in sequence [1].

Because no randomized clinical trials have yet to confer a clear survival benefit associated with any particular treatment or treatment regimen, and such trials are difficult to perform due to the rarity of MF and SS, this study was conducted in an effort to document existing treatment preferences, stratified by clinical stage, by dermatologists in the United States for MF and SS.

Table 1. TNMB Classification system for CTCL. [1, 29]
T T0 nondiagnostic (e.g., parapsoriasis)

T1 limited patch/plaque (<10 % total skin surface)

T2 generalized patch/plaque (≥10 % total skin surface)

T3 tumors

T4 erythroderma
N N0 lymph nodes clinically uninvolved.

N1 lymph nodes enlarged, histologically uninvolved (e.g. dermatopathic)

N2 lymph nodes clinically uninvolved, histologically involved

N3 lymph nodes enlarged and histologically involved
M M0 no visceral involvement

M1 visceral involvement
B B0 circulating atypical/Sézary cells (< 5 % of lymphocytes)

B1 circulating atypical/Sézary cells (≥ 5 % of lymphocytes)

Table 2. Clinical staging for CTCL.[1,29]
Stage T N M Study definition
Ia 1 0 0 limited patch/plaque
Ib 2 0 0 generalized patch/plaque
IIa 1-2 1 0 (not studied)
IIb 3 0-1 0 tumor stage
III 4 0-1 0 erythroderma/ Sézary syndrome
IVa 1-4 2-3 0 (not studied)
IVb 1-4 0-3 1 (not studied)


Methods

In November 2001 an anonymous multiple-choice survey was mailed to 6,178 individuals who were identified in a database purchased from the American Academy of Dermatology (AAD) as fellow members of the AAD between the ages of 35 and 65 in the United States of America. The return address displayed the name and institution of one author (M.A.F.). A postage-paid self-addressed envelope was provided. The four-page mailing contained a personalized cover letter, definitions of terms (Tables 1 and 2), and the two-page survey consisting of four demographic questions, requesting 1) The estimated annual number of patients with MF/SS evaluated, 2) The number of years practicing dermatology, 3) practice type (private practice/health maintenance organization (HMO)/community clinic, academic center, referral center for CTCL), and 4) State(s) in which dermatology care is provided. The physician was asked to rank a provided list of treatments for each disease stage (Table 2), including limited (<10 % body surface area) patch/plaque MF (stage Ia CTCL), generalized (≥10 % body surface area) patch/plaque MF (stage Ib), tumor stage MF (stage IIb), and erythrodermic MF/SS (stage III). Physicians were instructed to rank treatments based only on personal experience, and based on efficacy alone, without regard to compliance, cost, side effects, or review of the literature. Definitions of disease stage and efficacy were provided with the survey. Efficacy was defined as the ability to induce or maintain complete or partial clinical remission. Participants indicated each treatment's relative ranking by marking a number ranging from 1 (best treatment) to a value indicating worst treatment which differed depending on how many treatment options were available for each stage.

Treatments options for stage Ia CTCL included class I superpotent topical corticosteroids, carmustine total body solution, carmustine lesional ointment or solution, nitrogen mustard total body solution, nitrogen mustard lesional ointment or solution, bexarotene gel, PUVA, broadband UVB, and narrowband UVB. Choices for stage Ib CTCL included the above treatments, in addition to bexarotene oral, methotrexate, and interferon (α, β, γ). Stages IIb-III treatments included TSEB therapy, chlorambucil, methotrexate, photopheresis, and interferon (α, β, γ).

For the purpose of data analysis, a definitive highest ranking indicated a most effective treatment; if 2 treatments were equally ranked as number 1 relative to other treatments, then the response was considered indeterminate best (IB). Likewise, 2 equally lowest ranked treatments was considered an indeterminate worst (IW) response. If no treatments were ranked at all for a given stage of disease, the response was classified indeterminate (I). The data was analyzed using Microsoft Excel 9.0 (Microsoft, Inc.), SPSS 10.0 (SPSS, Inc.), and Systat 10.0 (SPSS, Inc.). Double checks for data entry discrepancies were performed on approximately 7 percent of the database.

The data was analyzed in aggregate and then stratified according to the 4 demographic variables listed above, including estimated number of patients per year evaluated with MF/SS (< 5, 5-20, > 20), years experience (< 10, 10-20, >20), practice type (private practice/HMO/community clinic, academic, CTCL referral center), selected States (CA, NY, PA, TX), and number of treatments ranked (2, >3).


Results

Among 6,178 surveys distributed, 1,399 surveys were received and analyzed.

Demographic data is summarized in Table 3. The majority of participants evaluate less than 5 patients per year with MF/SS (1,081, 77 %). Most dermatologists surveyed indicated 10 to 20 years practice experience (582, 42%), a private practice/HMO/community clinic practice setting (1,142, 82 %), with more responses from the State of California (173, 12 %) than any other State. Responses were received from all States and Puerto Rico.

Table 3. Demographic features of survey responders.


# (%)
Estimated number of SS/MF patients evaluated per year < 5 1081 (77)
5-20 222 (15)
>20 45 (3)
Years in practice <10 403 (29)
10-20 582 (42)
21-30 368 (26)
> 30 4 (<1)
Practice setting Private practice* 1142 (82)
Academic 185 (13)
CTCL Referral Center 12 (1)
SS= Sézary syndrome
MF=mycosis fungoides
*private practice/HMO/community clinic

The treatment choices of survey responders are summarized in Table 4.

Aggregate data (n=1,399) for the ranking of up to 9 treatments in stage Ia CTCL revealed PUVA to be the preferred treatment (436, 31 %). Nearly as many responses were classified as indeterminate best because two or more treatment choices were assigned an equivalent rating (394/645, 61 %). The least preferred treatment for stage Ia disease was class I superpotent topical corticosteroids (470, 34 %). The average number of treatments ranked was 3.7 for individuals ranking at least one treatment.

Table 4. Frequency of treatments selected as "most effective" or "least effective" among 1,399 survey responses.



# (%)
Stage Ia Most effective PUVA 436 (31)
Least effective Topical corticosteroids 470 (34)
Indeterminate Total 645 (46)

Indeterminate Best 394
Stage Ib Most effective PUVA 416 (30)
Least effective Topical corticosteroids 541 (39)
Indeterminate Total 700 (50)

Indeterminate Best 313
Stage IIb Most effective TSEB 203 (14)
Least effective methotrexate 81 (16)
Indeterminate Total 1148 (82)

Indeterminate Best 41
Stage III Most effective photopheresis 96 (7)
Least effective TSEB 60 (4.3)
Indeterminate Total 1180 (84)

Indeterminate Best 57
PUVA=psoralen + UVA photochemotherapy TSEB=total skin electron beam

Likewise, for the ranking of up to 12 treatments in stage Ib CTCL, PUVA was the most preferred treatment (416, 30 %). For Stage Ia CTCL, many responses were classified as indeterminate best because two or more treatment choices were assigned an equivalent rating (313/700, 45 %). The least preferred treatment for stage Ib CTCL was class I super potent topical corticosteroids (541, 39 %). The average number of treatments ranked was 4.1 for individuals ranking at least one treatment.

For the ranking of up to five treatments in stage IIb CTCL, TSEB therapy was the most frequently preferred treatment (203, 14 %). Forty-one responders ranked two or more treatments equally, comprising less than 4 percent of all indeterminate responses. The least preferred treatment for stage IIb CTCL was methotrexate (81, 6 %). The average number of treatments ranked was 2.2 for individuals ranking at least one treatment.

For the ranking of up to 5 treatments in stage III CTCL, photopheresis was the preferred treatment (96, 6.9 %) followed closely by TSEB (96, 6.3 %). Fifty-seven responders ranked two or more treatments equally, comprising less than 5 percent of all indeterminate responses. The least preferred treatment for stage IIb disease was also TSEB therapy (60, 4.3 %). The average number of treatments ranked was 2.3 for individuals ranking at least one treatment.

Stratified by each of the demographic variables, PUVA remained the preference for Stages Ia and Ib CTCL. Topical corticosteroids remained the least preferred treatment specified for Stages Ia and Ib. The greatest variation was noted for Stage III treatments: TSEB, rather than photopheresis, was slightly more frequently specified by physicians from the States of CA, PA, TX, and by physicians who practice in a private practice/HMO/community clinic setting. Those preferring photopheresis in Stage III CTCL were from academic or referral centers, ranked >3 treatments (indicating experience with these treatments), and included those with over 20 years experience, and those who evaluate more than 20 patients per year with MF/SS.

Many responders answered the demographic questions but left the treatment section completely blank (145/1399, 10 %), and approximately half of the responder group indicated preferences for Stage Ia and Ib, but left Stage IIb and III completely blank (718/1399, 51 %).


Conclusions

MF is classified as primary cutaneous lymphoma composed of CD4+ skin-homing T-helper cells. The annual incidence of MF has most recently been reported as 0.36/100,000 [21]. Patients with limited patches and plaques of MF appear to have a near-normal life expectancy compared to age-matched controls [22, 23, 24]. In contrast, SS is an aggressive lymphoma regarded by many as an erythrodermic leukemic variant of MF, with a reported 5-year survival of 33 percent [25]. Sézary syndrome is characterized by erythroderma and cerebriform lymphocytes (Sézary cells) in the peripheral blood, skin, and lymph nodes. The chance of developing extracutaneous disease for MF and SS generally correlates with the extent of cutaneous involvement; rates of 30-42 percent are seen for tumor or erythroderma patients, compared to 8 percent for generalized plaques [26]. Numerous treatment options are available for MF, but the comparative efficacy of treatments has not been extensively explored in randomized clinical trials.

This study was conducted to record the treatment preferences of a large number of practicing dermatologists for CTCL, stratified by four clinical stages. Overall, the data indicate PUVA was preferred for limited and generalized patch/plaque MF, with class I superpotent topical corticosteroids being the least favored, regardless of practice type, State, number of treatments ranked, patients evaluated per year with MF or SS, or years experience. TSEB therapy was preferred for tumor stage MF. Photopheresis was preferred for Stage III CTCL. However, the responses for tumor stage and erythrodermic CTCL, based on fewer treatment options and a majority of indeterminate responses, and thus should be viewed as less conclusive. For example, although 6.9 percent of physicians ranked photopheresis most effective and 6.3 percent ranked TSEB most effective for Stage III, 3.4 percent and 4.3 percent of physicians ranked photopheresis and TSEB least effective, respectively. However, the trend favoring photopheresis over TSEB was noted among the subsets of more experienced practitioners, among those who see a greater number of CTCL patients, and those practicing in academic or referral center settings.

That topical corticosteroids were ranked least effective for limited and generalized patch/plaque MF may underestimate its efficacy, as the common use of topical corticosteroids against atopic dermatitis, parapsoriasis, psoriasis, and other disorders that may mimic or precede clinically and histologically diagnostic MF may have excluded cases of early bona fide MF that were never conclusively diagnosed but nevertheless completely remitted by the application of topical corticosteroid. In fact, a comparison of response rates from published case series for topical corticosteroids, topical chemotherapy, UVB, and PUVA provides no obvious indication that corticosteroids would be inferior for limited patch/plaque MF [5].

In interpreting survey results, the potential significance of non-response bias warrants consideration. The authors believe that the response rate (22.6 %) in this study is satisfactory in the context of the rarity of CTCL and the broad sample population that was designed to minimize selection bias. We suspect the predominant reason for non-response is lack of experience in managing CTCL. This assumption is supported by the fact that the overall most common response was an indeterminate response, particularly for advanced stages of CTCL. Many surveys were returned with no ranking of treatment at all, especially for advanced stages, suggesting relatively greater lack of experience in treating advanced stage MF and SS. The survey was distributed to nearly every registered Fellow in the AAD between the ages of 35 and 65, many of whom are dermatologic surgeons, dermatopathologists, cosmetic dermatologists, or are general or pediatric dermatologists that would not typically manage MF/SS. Many physicians submitting indeterminate survey responses indicated they do not manage CTCL patients or that they routinely refer all of their CTCL cases to the local university. As further evidence to support this assumption, a comparison of responses from the first 1000 responders with the last 399 responders revealed a trend toward less experienced practitioners in the late responding group (not statistically significant; data not shown), but no difference in the ranking of most effective treatments for Stage Ia CTCL. In addition, many physicians ranked more than one treatment as most or least effective indicating that differences in comparative efficacy were not apparent. Based on these considerations, distributing the survey only to academic or referral centers would have been expected to reduce non-response bias but would also have increased selection bias, excluding practitioners with substantial experience that could not have been otherwise identified a priori. Our broad sampling was intended to identify treatment preferences based solely on personal clinical experience, because although physicians practicing in university referral centers possess the greatest concentration of experience, those experiences could vary from those of highly experienced private practitioners due to preferential participation by academic dermatologists in clinical trials. In addition, the results of non-federally funded clinical trials tend to be extensively publicized as part of the marketing of the manufacturer's products, whereas the cumulative experience of longtime practitioners is not promoted in comparable fashion.

Every treatment option in each disease stage was ranked both most effective and least effective by at least some physicians. This fact, in conjunction with the large number of indeterminate best responses for Stages Ia and Ib, suggests that, despite experience with different treatments, clear-cut differences in efficacy are often not obvious. Thus, topical therapies, phototherapy, photopheresis, radiation, and systemic therapy all potentially play a role in the treatment of MF/SS depending on individual circumstances. Future studies may also consider other relevant aspects such as cost and toxicity. Randomized, multi-center trials with positive results would help to create a broader standard of care for management of patients with CTCL, if such a standard exists based on available treatments at this time. Unfortunately, the expense of conducting such prospective studies for a relatively rare disorder such as CTCL likely precludes the possibility that data from such studies will be obtained in the near future. In the hierarchy of evidence, surveys are inferior to prospective clinical trials, representing a form of cross-sectional analysis.[27] However, survey data is comparable or superior to cases series and case reports, which currently dominate the published literature on therapy of CTCL. Thus, while survey results may be criticized as being akin to those of a popularity contest, they also offer a feasible, novel and clinically relevant perspective.

This study highlights the fact that many dermatologists do not encounter or manage MF/SS, underscoring the utility of specialized centers where a multi-disciplinary approach is often employed and the greatest experience is concentrated. Cooperation between dermatologists, dermatopathologists, hematopathologists, as well as medical, surgical, and radiation oncologists appears ideal for the optimal management of CTCL patients [28].

Acknowledgment:The study described in this manuscript was conceived and largely completed by the authors within the Department of Dermatology, University of Connecticut School of Medicine, Farmington, CT. The study was originally funded by the Department of Dermatology, University of Connecticut School of Medicine, Farmington, Connecticut, USA. The authors wish to thank Neil H. Willits, PhD and Dennis L. Fung, MD for assistance with statistical analysis, and the Department of Dermatology, University of California, Davis, California, USA, for additional funding support.

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