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Revisiting Low-Dose Total Skin Electron Beam Therapy in Mycosis Fungoides

International Journal of Radiation Oncology*Biology*Physics, 4, 81, pages e651 - e657

Purpose

Total skin electron beam therapy (TSEBT) is a highly effective treatment for mycosis fungoides (MF). The standard course consists of 30 to 36 Gy delivered over an 8- to 10-week period. This regimen is time intensive and associated with significant treatment-related toxicities including erythema, desquamation, anhydrosis, alopecia, and xerosis. The aim of this study was to identify a lower dose alternative while retaining a favorable efficacy profile.

Methods and Materials

One hundred two MF patients were identified who had been treated with an initial course of low-dose TSEBT (5–<30 Gy) between 1958 and 1995. Patients had a T stage classification of T2 (generalized patch/plaque, n = 51), T3 (tumor, n = 29), and T4 (erythrodermic, n = 22). Those with extracutaneous disease were excluded.

Results

Overall response (OR) rates (>50% improvement) were 90% among patients with T2 to T4 disease receiving 5 to <10 Gy (n = 19). In comparison, OR rates between the 10 to <20 Gy and 20 to <30 Gy subgroups were 98% and 97%, respectively. There was no significant difference in median progression free survival (PFS) in T2 and T3 patients when stratified by dose group, and PFS in each was comparable to that of the standard dose.

Conclusions

OR rates associated with low-dose TSEBT in the ranges of 10 to <20 Gy and 20 to <30 Gy are comparable to that of the standard dose (≥ 30 Gy). Efficacy measures including OS, PFS, and RFS are also favorable. Given that the efficacy profile is similar between 10 and <20 Gy and 20 and <30 Gy, the utility of TSEBT within the lower dose range of 10 to <20 Gy merits further investigation, especially in the context of combined modality treatment.

Cutaneous lymphomas, Mycosis fungoides, Radiotherapy, Low-dose total skin electron beam therapy, T-cell lymphoma.

Introduction

Mycosis fungoides (MF) is an extranodal non-Hodgkin’s lymphoma of T-cell origin with primary cutaneous involvement (1) . It is the most common primary lymphoma of the skin. It is an uncommon condition with an incidence of 6.4 per 1 million persons in the United States (2) . The presentation of MF is heterogeneous. In the classic form, patients often present with cutaneous eruptions ranging from pruritic patches to plaques, tumors, or erythroderma. Prognosis is related directly to the clinical stage at diagnosis with the most predictive factors being patient age, T stage classification, and presence of extracutaneous disease (3) . Staging is based on a tumor-node-metastasis-blood (TNMB) classification system initially developed by the Mycosis Fungoides Cooperative Group and National Cancer Institute, which was published in 1979 (4) . This system has proven to be extremely useful, and it is the foundation for the staging and classification of patients with MF or Sézary syndrome. The criteria were revised in 2007 in a joint report from the International Society for Cutaneous Lymphomas and the European Organization of Research and Treatment of Cancer (EORTC) (5) . The revised staging system has recently been adopted by the American Joint Committee on Cancer (6) .

Historically, radiation therapy achieves very high response rates and remains the single most effective modality in the treatment of MF. Electron beam therapy is preferable to X-ray (photon) therapy because of its limited depth of penetration. This limits the side effect profile of the treatment (7) . Total skin electron beam therapy (TSEBT) was introduced as a treatment for patients with MF in 1952 (8) . Early patients were treated with total doses as low as 8 Gy. Excellent responses were recorded at this dose, with minimal associated toxicity. Relapses eventually occurred, and doses were gradually increased. By the mid 1970s, the standard dose had increased to 36 Gy, administered over an 8- to 10-week period (9) .

Although the likelihood of a CR increases with the standard dose, it is associated with greater toxicity (10) . The most common acute complications of standard dose TSEBT are erythema and dry desquamation. Intermediate and long-term side effects include partial alopecia and temporary loss of fingernails and toenails (11) . Most patients report the inability to sweat properly for 6 to 12 months following therapy and complain of xerosis (12) and (13). Because of the risk for skin atrophy and potential necrosis, there has been reluctance to administer more than two conventional courses of TSEBT in a patient’s lifetime (14) . Since most patients will have recurrent disease with the standard dose, this limitation restricts the use of this effective therapy.

There has been recent interest in revisiting the effectiveness of lower dose TSEBT in the management of patients with MF (15) . In comparison with the standard 8- to 10- week course of 30 to 36 Gy, lower dose treatment has several advantages. It may limit radiation-related toxicities, expand options for combination or sequential therapies, and permit the administration of multiple treatment courses. A shorter regimen would also improve access to this treatment modality.

In this study, we retrospectively reviewed the Stanford University experience treating patients with stage T2 to T4 MF, using an initial course of low-dose TSEBT (5–<30 Gy). We also reviewed the outcomes of those who received subsequent courses of TSEBT following the initial low-dose course. Our goal was to identify a low-dose range of TSEBT with a favorable efficacy profile.

Methods and Materials

Patients

We used the comprehensive database of the Stanford Multidisciplinary Cutaneous Lymphoma Program to identify patients with MF who received low-dose TSEBT (5–<30 Gy) in the Department of Radiation Oncology from 1958 to 1996. The majority of patients receiving the lower dose did so prior to widespread adoption of the 30 to 36 Gy standard regimen. All patients had a diagnosis of MF confirmed in the Cutaneous Lymphoma Clinic at Stanford. For classification and staging, patients underwent a thorough physical examination, complete blood cell count assay with examination for Sézary cells, general chemistry panel, and chest radiography. When indicated, additional studies including bone marrow biopsy or lymph node biopsy or other imaging studies were used to evaluate for extracutaneous involvement. A lymph node biopsy or fine needle aspiration was performed in those patients with palpable lymphadenopathy suspicious for involvement by MF. Suspected involvement of any visceral sites was confirmed by biopsy whenever possible. All patients were staged according to the TNMB classification system (4) and (5).

Study design

We limited this analysis to patients with stage T2–4 N0–1 M0B0 disease at the time of TSEBT initiation. Only patients receiving their first course of TSEBT at doses ranging from 5 to <30 Gy were included. Patients did not receive systemic therapy during the TSEBT course, and they remained off therapy unless their disease worsened significantly during the follow-up period. For the purpose of comparison, data were also analyzed for a cohort of patients with T2–4 N0–1 M0B0 disease who were treated with standard doses (≥30 Gy) of TSEBT from 1970 to 2007.

We also identified a cohort of patients who were retreated with low-dose TSEBT. Patients were given the additional course upon disease worsening or relapse following the initial low-dose treatment. Only those with stage T2–4 N0–1 M0B0 disease were included, and the outcomes from these additional courses were analyzed separately. All aspects of the study design and analysis were reviewed and approved by the Stanford Institutional Review Board.

Response criteria

Initial clinical responses were determined using a global assessment of response. This was performed approximately 4 to 6 weeks after completing TSEBT, when the acute skin reactions associated with radiotherapy had subsided. Complete response (CR) was defined as clinical resolution of all cutaneous MF lesions, and partial response (PR) was defined as greater than a 50% clearing of cutaneous lesions compared to baseline. Patients with less than 50% improvement were considered to have stable disease. Complete responders were determined to have relapsed at the time of biopsy proven recurrence of MF or clinical evidence of relapse without histopathologic confirmation. Disease progression was defined as increase in TNMB classification or death due to disease.

Statistical analysis

All survival curves were calculated from the date of initiation of TSEBT and were displayed as Kaplan-Meier plots. Outcome measures were analyzed within each T classification stratified by dose group. Differences in actuarial curves were determined using the log-rank test. Within each T stage, all paired comparisons for the four dose groups were carried out with Sidak multiple-comparison adjustment. Progression-free survival (PFS) was calculated from date of TSEBT initiation until documentation of change in TNMB status or death due to any cause. In complete responders, relapse-free survival (RFS) was calculated from the start date of TSEBT until documentation of disease relapse or death from any cause.

Results

One hundred two patients (68 male, 34 female) qualified for inclusion in this analysis. Of this cohort, 51 patients had stage T2, 29 patients had T3, and 22 patients had T4 disease at initiation of TSEBT. Median age at initiation was 59 years old (range, 21–90 years), and median time from diagnosis to TSEBT was 4 months (range, 0–224 months). The majority of patients were treated prior to the adoption of the >30 Gy standard (median, 1965; range, 1958–1993). Most patients had failed one prior therapy for MF before starting TSEBT, but the range for the group included up to six prior treatments.

Patients were grouped according to those receiving 5 to <10 Gy, 10 to < 20 Gy, and 20 to <30 Gy. Clinical response rates are described in Table 1 . Although nearly all patients (96%) had an objective clinical response (PR or CR), response rates were generally higher among those receiving 10 to <20 Gy and 20 to <30 Gy than among patients receiving <10 Gy. As expected, CR rates were reduced in the lower dose groups compared to the standard dose (≥30 Gy). Median number of prior treatments was not different when comparing low-dose groups.

Table 1 Initial course clinical response by dose

T class or range Response No. of patients/total (%) per dose group
5–<10 Gy 10–<20 Gy 20–<30 Gy 5–<30 Gy
T2 CR 1/7 (14) 13/25 (52) 7/19 (37) 21/51 (41)
PR 5/7 (71) 11/25 (44) 12/19 (63) 28/51 (55)
OR 6/7 (85) 24/25 (96) 19/19 (100) 49/51 (96)
T3 CR 2/8 (25) 1/14 (7) 2/7 (29) 5/29 (17)
PR 5/8 (63) 13/14 (93) 5/7 (71) 23/29 (79)
OR 7/8 (88) 14/14 (100) 7/7 (100) 28/29 (96)
T4 CR 0/4 (0) 4/12 (33) 2/6 (33) 6/22 (27)
PR 4/4 (100) 8/12 (67) 3/6 (50) 15/22 (68)
OR 4/4 (100) 12/12 (100) 5/6 (83) 21/22 (95)
T2–T4 CR 3/19 (16) 18/51 (35) 11/32 (34) 32/102 (31)
PR 14/19 (74) 32/51 (63) 20/32 (63) 66/102 (65)
OR 17/19 (90) 50/51 (98) 31/32 (97) 98/102 (96)

Abbreviations: CR = complete response (clinical resolution of all cutaneous lesions); PR = partial response (>50% resolution of cutaneous lesions defined by the physicians global assessment); OR = Overall response (PR plus CR).

Overall survival (OS) was analyzed within each T stage ( Fig. 1 ). When patients were stratified by dose group and compared using the log-rank test, there were no significant differences in OS among T2 and T3 patients ( Table 2 ). Similar trends were noted in the analysis of PFS ( Table 3 , Fig. 2 ). Although differences in OS and PFS were noted when comparing dose groups in the T4 patient cohort using the log-rank test, all of the paired comparisons of dose groups using Sidak method for multiple comparison adjustment did not show any to be statistically significant.

gr1

Fig. 1 Actuarial OS is shown stratified by dose category in patients with T2 (a), T3 (b), and T4 (c) disease. Differences in actuarial curves were not statistically significant by the log-rank test or when adjusted for multiple comparisons within the log rank test.

Table 2 Median OS by T classification

T class OS (years) per dose group (95% CI) p value
5–<10 Gy 10–<20 Gy 20–<30 Gy ≥30 Gy
2 19.0 (1.5–34.0) 9.0 (6.7–18.0) 6.8 (2.5–12.8) 13.2 (9.4–15.6) 0.121
3 2.0 (0.1–6.1) 2.7 (0.5–8.0) 2.7 (0.5–5.2) 4.8 (3.1–6.1) 0.167
4 0.8 (0.1–10.2) 9.8 (2.1–19.6) 6.3 (0.9–14.4) 4.6 (2.2–10.5) 0.046

Abbreviation: CI = confidence interval.

Table 3 Median PFS by T classification

T class PFS (years) per dose group (95% CI) p value
5–<10 Gy 10–<20 Gy 20–<30 Gy ≥30 Gy
2 14.1 (1.2–23.6) 8.0 (2.8–14.6) 5.2 (2.2–7.3) 8.5 (6.3–11.6) 0.243
3 2.0 (0.1–5.3) 2.7 (0.5–7.6) 2.7 (0.5–5.2) 2.9 (1.8–5.3) 0.3
4 0.8 (0.1–2.5) 9.8 (2.1–17.1) 6.3 (0.9–14.4) 4.6 (2.2–10.5) <0.001

Abbreviation: CI = confidence interval.

gr2

Fig. 2 Actuarial PFS is shown stratified by dose category in patients with T2 (a), T3 (b), and T4 (c) disease. Differences in actuarial curves were not statistically significant by the log-rank test or when adjusted for multiple comparisons within the log rank test.

RFS generally improved with higher radiation doses ( Table 4 ). Due to low patient numbers in the 5 to <10 Gy dose group, is was not possible to compare RFS in the 5 to <10 Gy and 10 to <20 Gy cohorts.

Table 4 Median RFS period by dose category

Dose group No. of patients RFS period (months) 95% CI
5–<10 Gy 3 12.0 6.5–12.1
10–<20 Gy 18 25.7 10.9–43.4
20–<30 Gy 11 29.3 4.3–85.6
≥30 Gy 122 22.2 13–33

Abbreviation: CI = confidence interval.

Of the 102 patients in the initial treatment group, 36 patients (18 patients with stage T2, 11 patients with T3, and 7 patients with T4 disease) received an additional course of TSEBT. Of these patients, 7 patients achieved a CR following the initial course. Median interval between the initial and additional courses was 9 months (range, 2–97 months). The median dose for the additional courses was 12 Gy (range, 8–34 Gy).

All 36 patients who were treated with an additional course of TSEBT responded ( Table 5 ). However, the CR rates for these patients were lower than those for the initial course of TSEBT. All patients in the additional dose group had an objective clinical response.

Table 5 Additional course clinical response by dose

T class or range Response No. of patients/total (%) per dose group
5–<10 Gy 10–<20 Gy 20–<30 Gy
T2 CR 1/6 (17) 1/10 (10) 2/2 (100)
PR 5/6 (83) 9/10 (90) NA
OR 6/6 (100) 10/10 (100) 2/2 (100)
T3 CR NA NA NA
PR 2/2 (100) 7/7 (100) 2/2 (100)
OR 2/2 (100) 7/7 (100) 2/2 (100)
T4 CR 1/3 (33) 1/4 (25) NA
PR 2/3 (67) 3/4 (75) NA
OR 3/3 (100) 4/4 (100) NA
T2–T4 CR 2/11 (18) 2/21 (10) 2/4 (50)
PR 9/11 (82) 19/21 (90) 2/4 (50)
OR 11/11 (100) 21/21 (100) 4/4 (100)

Abbreviations: CR = Complete response (clinical resolution of all cutaneous lesions); PR = partial response (> 50% resolution of cutaneous lesions as defined by the physicians global assessment); OR = overall response (PR plus CR); NA = XXXX.

Discussion

TSEBT is a well-established treatment for MF, with many large institutional case series documenting its effectiveness (9) and (10). Historically, TSEBT doses evolved from 8 Gy to 36 Gy as acute tolerance for higher doses was demonstrated and CR rates improved. Excellent overall response (OR) rates have been reported at all dose levels, but CR and RFS rates are more dose dependent (7) .

The correlation between CR rate and dose is demonstrated in our data. Among patients with T2 to T4 disease, CR rates (per dose group) were 16% (5–<10 Gy, n =19), 35% (10–<20 Gy, n = 51), and 34% (20–<30 Gy, n = 22). Although there appears to be a positive correlation between increased dose and CR rate, these differences were not statistically significant. However, CR rates increased to 62% among patients with T2 to T4 disease once the dose exceeded 30 Gy (n = 197). In light of this and other published data, TSEBT at doses ranging from 30 to 36 Gy is considered among the most reliable treatments for MF with respect to its ability to elicit a complete cutaneous response and has led to the development of the current EORTC (16) and NCCN (17) guidelines recommending that total doses range between 30 and 36 Gy.

The efficacy of TSEBT correlates strongly with disease severity as described by T stage classification. The difference is most apparent when comparing T2 and T3 disease. Numerous studies have documented higher response rates among patients with T2 in comparison to T3 disease when treated with doses exceeding 30 Gy (9) and (18) or in studies where TSEBT is combined with nitrogen mustard (19) , chemotherapy (20) ,or interferon (21) .

Our data demonstrate that low-dose TSEBT (5–<30 Gy) was more effective in T2 than in T3 disease (CR rate, 41% for T2 [n = 51] vs. 17% for T3 [n = 29]). CR rates, however, could not be correlated with radiation dose due to the small number of patients in each cohort.

Mycosis fungoides is an indolent disease with a long natural history. The majority of patients have (or develop) generalized skin involvement. Although a CR is the preferred outcome for any therapeutic modality, it is particularly difficult to achieve in this disease. The NCCN guidelines recommend that patients with stage IB (T2) disease and some with IIB (T3) disease be treated primarily with skin-directed therapies (17) . These include topical chemotherapies (i.e., nitrogen mustard), topical corticosteroids, narrow band UVB, and psoralen plus ultraviolet-A (PUVA). CR rates associated with topical steroids are reported to be 25% in stage IB (22) . CR rates are somewhat higher with nitrogen mustard and reportedly range from 39% to 68% in T2 disease and 23% to 39% in T3 (19) and (23). Although CR rates associated with narrow band UVB (24) and (25) and PUVA (25) and (26) range from 54% to 75% and 59% to 81%, respectively, interpretation of the data is limited by low patient numbers. In addition, it is difficult to compare response rates between different therapies or published reports, and very few randomized clinical trials have been reported for this rare disease. The selection of a particular treatment is influenced by numerous factors including disease distribution, lesion thickness, and institutional preference. Despite these variations, it is clear that CR rates are suboptimal even for the most effective MF therapies.

Regardless of modality, MF is often a chronic disease, and most patients will require multiple therapies over the course of a lifetime. As each treatment is associated with cumulative skin toxicity, it is important to maximize the benefit of each therapy.

Although a CR is preferable, a clinically meaningful response (>50% improvement in skin assessment) to a given therapy is of significant benefit. This is particularly relevant in patients with MF, where a reduction in disease burden often translates into symptomatic relief, enhanced quality of life, and improved ability to control remaining disease with topical therapies. Our data demonstrate that low-dose TSEBT produces predictably high OR rates (>96%) across all low-dose radiation subgroups (5–<30 Gy) and T classes (T2–T4). When separated by dose category, OR rates approach 100% in the 10 to <20 Gy and 20 to <30 Gy dose groups. Among complete responders, FFR was not significantly different between the low and higher (≥30 Gy) dose groups. OR rates are excellent (100%) in the additional dose group.

The efficacy of low-dose TSEBT we report in this series exceeds that of other standard skin-limited therapies recommended in the NCCN guidelines (17) . Among patients with T2 disease, OR rates for topical corticosteroids, nitrogen mustard, and narrow band UVB are 57% (22) , 72% (27) , and 75% (28) , respectively. In addition, the near 100% OR to low-dose TSEBT in patients with T2 to T4 disease is superior to that of any standard skin-directed or systemic therapy.

Although OR rates are high in all dose categories, response duration is likely dose dependent. A recent prospective study examined the efficacy of 4 Gy TSEBT fractionated over the course of 4 days in patients with MF for whom therapy had recently failed to obtain a full remission after standard PUVA. Although 88% of patients responded (n = 9), the duration of response was unacceptably low (median, 2.7 months; range, 1–3.5 months). As a consequence, the study was terminated after the initial review of 10 patients (15) . Response durability was also disappointing in a study by Neelis and colleagues (29) , examining the efficacy of electron beam radiation to specific MF lesions at a dose of 2 Gy given twice over 2 to 3 days. Of 17 treated lesions, 12 lesions failed to achieve a CR after 2 months, and 11 lesions required further treatment at a higher dose because of poor response durability. In light of these two studies, it is likely that TSEBT doses should exceed 4 Gy to maximize CR rates and response duration.

Despite the efficacy and potential therapeutic benefit of low-dose TSEBT, it is critical that PFS and OS are not compromised in comparison to the higher dose standard. Our OS data do not show a significant difference between the standard and low-dose regimens. Progression free survival is more challenging to estimate given the limitations of a retrospective study. Although tools used to assess response to treatment in MF have changed with time, TNMB changes are well documented in our database. Given our definition of PFS (TNMB change or death from any cause), median PFS rate is not statistically different between low-dose and standard dose groups.

The likely drawback of low-dose TSEBT is the decreased CR rate and reduced response duration. These drawbacks, however, are manageable. Theoretically, it might be possible to improve CR rates through the combined use of a radiation sensitizer such as vorinostat, a histone deacetylase inhibitor. This medication class may act as a radiosensitizing agent by modulating the expression of double- and single-strand DNA repair proteins such as KU67, KU86, H2AX, and Rad50 (30), (31), and (32). It is likely that increased radiosensitivity could translate into higher response rates and response durability. Response duration could be further improved with localized use of topical therapies or other systemic agents.

Conclusions

In summary, low-dose TSEBT at doses in the range of 10 to <20 Gy and 20 to <30 Gy are comparable to the standard dose regimen in terms of OR, OS, PFS, and RFS. Given that the efficacy profiles of 10 to <20 Gy and 20 to <30 Gy appear to be similar, the therapeutic use of TSEBT within the lower dose range of 10 to <20 Gy merits further exploration. Although CR rates are lower than the traditional dose, further study is warranted to identify combination therapies to help to improve CR rates and response durability.

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Footnotes

Department of Dermatology, Stanford Cancer Center, Stanford, California

Department of Radiation Oncology, Stanford Cancer Center, Stanford, California

Reprint requests to: Cameron Harrison, M.D., Stanford Department of Dermatology, 450 Broadway Street, Pavilion C, Redwood City, CA 94063. Tel: (650) 721-7186; Fax: (650) 721-3464

Author contributions: Drs. Hoppe, Kim, and Harrison had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Drs. Kim, Hoppe, and Navi. Acquisition of data: Drs. Navi, Riaz, Harrison, and Young. Analysis and interpretation of data: Drs. Navi, Harrison, Riaz, Young, Kim, and Hoppe. Manuscript draft: Dr. Harrison. Critical revision for intellectual content: Drs. Kim and Hoppe. Statistical analysis: Drs. Riaz and Harrison and B. Lingala. Study supervision: Drs. Kim and Hoppe.

Conflict of interest: none.