Ultrahypofractionated Low-Dose Total Skin Electron Beam in Advanced-Stage Mycosis Fungoides and Sézary Syndrome.

PURPOSE: The aim of this study was to assess the safety and efficacy of an ultrahypofractionated low-dose total skin electron beam therapy (TSEBT) regimen in patients with advanced mycosis fungoides (MF) or Sézary syndrome (SS). METHODS AND MATERIALS: In this multicenter observational study from 5 German centers, 18 total patients with MF or SS underwent TSEBT with a total dose of 8 Gy in 2 fractions. The primary endpoint was the overall response rate. RESULTS: Fifteen of 18 patients with stage IIB-IV MF or SS were heavily pretreated with a median of 4 prior systemic therapies. The overall response rate was 88.9% (95% confidence interval [CI], 65.3-98.6), with 3 complete responses (16.9%; 95% CI, 3.6-41.4). At a median follow-up period of 13 months, the median time to next treatment (TTNT) was 12 months (95% CI, 8.2-15.8), and the median progression-free survival was 8 months (95% CI, 2-14). A significant reduction in the modified severity-weighted assessment tool, total Skindex-29 score (Bonferroni-corrected P < .005), and all subdomains (Bonferroni-corrected P < .05) was observed after TSEBT. Half of the irradiated patients (n = 9) developed grade 2 acute and subacute toxicities. One patient had confirmed grade 3 acute toxicity. Chronic grade 1 toxicity has been observed in 33% of patients. Patients with erythroderma/SS or prior radiation therapy appear at higher risk of skin toxicities. CONCLUSIONS: TSEBT with 8 Gy in 2 fractions achieves good disease control and symptom palliation with acceptable toxicity, greater convenience, and fewer hospital visits.

Acute and sub-acute toxicity profile of ultra-hypofractionated low-dose total skin electron beam with two 4 Gy fractions for cutaneous T cell lymphoma.

PURPOSE: Low-dose total skin electron beam therapy (TSEBT) over 3 weeks has proved to be a safe and effective treatment for cutaneous T cell lymphomas (CTCL). In this prospective trial, we examined the feasibility of ultra-hypofractionated low-dose TSEBT regimen in two fractions with 4 Gy combined with systemic therapy to minimize the number of visits to radiation centers. PATIENTS AND METHODS: Six patients with mycosis fungoides (MF) or Sézary syndrome (SS) received TSEBT with a total radiation dose of 8 Gy in two fractions between April 2020 and June 2020. Patient and treatment characteristics, tumor burden, the impact on the quality of life using Skindex-29 questionnaires, and acute toxicities were analyzed. RESULTS: During TSEBT, all patients developed grade 1 toxicities while two patients developed grade 2 toxicities. One patient experienced sepsis. The most common adverse effects were erythema and edema. All grade 2 toxicities regressed after 4 weeks following TSEBT. Based on the reported symptoms measured by Skindex-29, we detected a significant reduction in total Skindex-29 score after 8 weeks of radiation (P = 0.03), particularly in the symptoms (P = 0.01) and emotional domains (P = 0.04). CONCLUSION: Ultra-hypofractionated low-dose TSEBT followed by systemic therapy seems to be a safe and feasible alternative to conventional fractionated TSEBT for patients with MF/SS. The skin tumor burden and the health-related quality of life have been significantly improved within 8 weeks following radiotherapy.

Low-dose total skin electron beam therapy: Quality of life improvement and clinical impact of maintenance and adjuvant treatment in patients with mycosis fungoides or Sezary syndrome.

PURPOSE: Total skin electron beam therapy (TSEBT) has proved to be a safe and effective treatment for cutaneous T­cell lymphomas. Here, we examined the impact of this treatment on patient quality of life and outcome. PATIENTS AND METHODS: Forty-four patients with mycosis fungoides (MF) or Sezary syndrome (SS) received 48 TSEBT courses with a median dose of 12 Gy within the past 8 years at our institute. Patient and treatment characteristics for these cases as well as the impact of TSEBT on quality of life and duration of response were retrospectively analyzed and compared. RESULTS: The median modified Severity-Weighted Assessment Tool score before the start of TSEBT was 44. The overall response rate was 88%, with a complete response (CR) rate of 33%. The median follow-up period was 13 months. The median duration of response (DOR) and progression-free survival (PFS) for the entire cohort were 10 months and 9 months, respectively. Patient-reported symptom burden was measured with the Dermatological Life Quality Index and Skindex-29 questionnaires. The mean symptom reductions were 6 ± 8 (P = 0.005) and 21 ± 24 (P = 0.002), respectively. In the Functional Assessment of Cancer Therapy-General Assessment, significant improvements in the emotional (P = 0.03) domains were observed after TSEBT. Patients who received maintenance or adjuvant treatments had a longer PFS (P = 0.01). CONCLUSION: TSEBT improved disease symptoms and significantly improved emotional domains of patients' quality of life in patients with MF or SS. In addition, our results indicate that maintenance or adjuvant therapy after TSEBT may improve the PFS.

Standardization of regimens in Narrowband UVB and PUVA in early stage mycosis fungoides: position paper from the Italian Task Force for Cutaneous Lymphomas.

UV-based (PUVA and narrowband UVB) phototherapy is broadly and commonly used in the treatment of Cutaneous T-cell Lymphomas (CTCL), yet unfortunately, the evidence for the efficacy of these treatments is based only on case series or prospective but non-randomized studies. Therefore, no internationally approved guidelines exist and no standardization of schedules has been proposed. Recently, consensus guidelines have been published by the United States Cutaneous Lymphoma Consortium. The aim of this study was to review the biological and clinical evidences on PUVA and NB-UVB in CTCL and to critically evaluate acceptability and feasibility of these guidelines in the real-life setting from the perspective of the Cutaneous Lymphoma Task Force of the Italian Lymphoma Foundation (Fondazione Italiana Linfomi, FIL).

Total Skin Electron Beam for Primary Cutaneous T-cell Lymphoma.

PURPOSE: Recent trials with low-dose total skin electron beam (TSEB) therapy demonstrated encouraging results for treating primary cutaneous T-cell lymphoma (PCTCL). In this study, we assessed the feasibility of different radiation doses and estimated survival rates of different pathologic entities and stages. METHODS AND MATERIALS: We retrospectively identified 45 patients with PCTCL undergoing TSEB therapy between 2000 and 2015. Clinical characteristics, treatment outcomes, and toxicity were assessed. RESULTS: A total of 49 courses of TSEB therapy were administered to the 45 patients. There were 26 pathologically confirmed cases of mycosis fungoides (MF) lymphoma, 10 cases of Sézary syndrome (SS), and 9 non-MF/SS PCTCL patients. In the MF patients, the overall response rate (ORR) was 92% (50% complete remission [CR]), 70% ORR in SS patients (50% CR), and 89% ORR in non-MF/SS patients (78% CR). The ORR for MF/SS patients treated with conventional dose (30-36 Gy) regimens was 92% (63% CR) and 75% (25% CR) for low-dose (<30-Gy) regimens (P=.09). In MF patients, the overall survival (OS) was 77 months with conventional dose regimens versus 14 months with low-dose regimens (P=.553). In SS patients, the median OS was 48 versus 16 months (P=.219), respectively. Median event-free survival (EFS) for MF in conventional dose patients versus low-dose patients was 15 versus 8 months, respectively (P=.264) and 19 versus 3 months for SS patients (P=.457). Low-dose regimens had shorter treatment time (P=.009) and lower grade 2 adverse events (P=.043). A second TSEB course was administered in 4 MF patients with 100% ORR. There is a possible prognostic impact of supplemental/boost radiation (P<.001); adjuvant treatment (P<.001) and radiation tolerability (P=.021) were detected. CONCLUSIONS: TSEB therapy is an efficacious treatment modality in the treatment of several forms of cutaneous T-cell lymphoma. There is a nonsignificant trend to higher and longer clinical benefit for MF and SS patients receiving conventional dose. Low-dose TSEB regimens are well tolerated and achieve short-term palliation.

Low-dose (10-Gy) total skin electron beam therapy for cutaneous T-cell lymphoma: an open clinical study and pooled data analysis.

PURPOSE: Cutaneous T-cell lymphomas (CTCLs) are dominated by mycosis fungoides (MF) and Sézary syndrome (SS), and durable disease control is a therapeutic challenge. Standard total skin electron beam therapy (TSEBT) is an effective skin-directed therapy, but the possibility of retreatments is limited to 2 to 3 courses in a lifetime due to skin toxicity. This study aimed to determine the clinical effect of low-dose TSEBT in patients with MF and SS. METHODS AND MATERIALS: In an open clinical study, 21 patients with MF/SS stages IB to IV were treated with low-dose TSEBT over <2.5 weeks, receiving a total dose of 10 Gy in 10 fractions. Data from 10 of these patients were published previously but were included in the current pooled data analysis. Outcome measures were response rate, duration of response, and toxicity. RESULTS: The overall response rate was 95% with a complete cutaneous response or a very good partial response rate (<1% skin involvement with patches or plaques) documented in 57% of the patients. Median duration of overall cutaneous response was 174 days (5.8 months; range: 60-675 days). TSEBT-related acute adverse events (grade 1 or 2) were observed in 60% of patients. CONCLUSIONS: Low-dose (10-Gy) TSEBT offers a high overall response rate and is relatively safe. With this approach, reirradiation at times of relapse or progression is likely to be less toxic than standard dose TSEBT. It remains to be established whether adjuvant and combination treatments can prolong the beneficial effects of low-dose TSEBT.

Improvement in peripheral blood disease burden in patients with Sézary syndrome and leukemic mycosis fungoides after total skin electron beam therapy.

BACKGROUND: There is a paucity of effective therapies for patients with Sézary syndrome and advanced mycosis fungoides with peripheral blood involvement. Total skin electron beam (TSEB) radiation therapy is an extremely effective skin-directed therapy for these patients, but, until recently, it was thought not to signifcantly affect the peripheral blood malignant T-cell population. OBJECTIVE: We conducted this study to determine if TSEB has therapeutic effect on the peripheral blood in patients with advanced mycosis fungoides and Sézary syndrome. METHODS: All patients on stable medication regimens seen in our photopheresis facility who received TSEB therapy between January 2008 and October 2011 at Temple University Hospital, Philadelphia, PA, were analyzed retrospectively for improvement in the peripheral blood, as documented by flow cytometry. RESULTS: Six of 11 patients achieved 50% or greater decrease in their peripheral blood malignant T-cell population after TSEB therapy, for an overall response rate of 55%. Within the group of patients who had a response in the skin, 67% also had a response in the peripheral blood. LIMITATIONS: This analysis is limited in 3 ways. First, the sample described is small. Second, the results may be confounded by the fact that each patient was on other systemic therapies in addition to TSEB, albeit stable pre-existing regimens. The time interval between completion of TSEB therapy and repetition of flow cytometry was not standardized among patients, which may result in an underestimation of the overall response to TSEB therapy. CONCLUSION: In patients with advanced mycosis fungoides and Sézary syndrome, the peripheral blood tumor burden may improve after treatment with TSEB.

Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma.

PURPOSE: Cutaneous T-cell lymphoma (CTCL) is a radiosensitive tumor. Presently, treatment with radiation is given in multiple fractions. The current literature lacks data that support single-fraction treatment for CTCL. This retrospective review assesses the clinical response in patients treated with a single fraction of radiation. METHODS AND MATERIALS: This study reviewed the records of 58 patients with CTCL, primarily mycosis fungoides, treated with a single fraction of palliative radiation therapy (RT) between October 1991 and January 2011. Patient and tumor characteristics were reviewed. Response rates were compared using Fisher's exact test and multiple logistic regressions. Survival rates were determined using the Kaplan-Meier method. Cost-effectiveness analysis was performed to assess the cost of a single vs a multifractionated treatment regimen. RESULTS: Two hundred seventy individual lesions were treated, with the majority (97%) treated with ≥ 700 cGy; mean follow-up was 41.3 months (range, 3-180 months). Response rate by lesion was assessed, with a complete response (CR) in 255 (94.4%) lesions, a partial response in 10 (3.7%) lesions, a partial response converted to a CR after a second treatment in 4 (1.5%) lesions, and no response in 1 (0.4%) lesion. The CR in lower extremity lesions was lower than in other sites (P=.0016). Lesions treated with photons had lower CR than those treated with electrons (P=.017). Patients with lesions exhibiting large cell transformation and tumor morphology had lower CR (P=.04 and P=.035, respectively). Immunophenotype did not impact response rate (P=.23). Overall survival was significantly lower for patients with Sézary syndrome (P=.0003) and erythroderma (P<.0001). The cost of multifractionated radiation was >200% higher than that for single-fraction radiation. CONCLUSIONS: A single fraction of 700 cGy-800 cGy provides excellent palliation for CTCL lesions and is cost effective and convenient for the patient.

Total skin electron beam and non-myeloablative allogeneic hematopoietic stem-cell transplantation in advanced mycosis fungoides and Sezary syndrome.

PURPOSE: Transformed mycosis fungoides (MF) and Sézary syndrome (SS) are currently incurable. We studied the safety and efficacy of total skin electron beam with allogeneic hematopoietic stem-cell transplantation (HSCT) in patients with cutaneous T-cell lymphoma (CTCL). PATIENTS AND METHODS: Nineteen patients with advanced CTCL (median age, 50 years; four prior therapies) underwent total skin electron beam radiation followed by allogeneic HSCT between July 2001 and July 2008. Sixteen patients were conditioned with fludarabine (125 mg/m(2)) and melphalan (140 mg/m(2)) plus thymoglobulin (for mismatched donors). Graft-versus-host disease (GVHD) prophylaxis was with tacrolimus/mini methotrexate. RESULTS: Eighteen patients experienced engraftment, and one died as a result of sepsis on day 16. Median time to recovery of absolute neutrophil count (ANC) was 12 days. Fifteen achieved full donor chimerism, 12 had acute GVHD, and 12 were treated for chronic GVHD. The overall intent-to-treat response was 68%, and the complete response rate was 58%. Four of six patients died in complete remission as a result of bacterial sepsis (n = 2), chronic GVHD and fungal infection (n = 1), or lung cancer (n = 1); only two died as a result of progressive disease. Eight experienced relapse in skin; five regained complete response with reduced immunosuppression or donor lymphocyte infusions. Eleven of 13 are currently in complete remissions, with median follow-up of 19 months (range, 1.3 to 8.3 years). Median overall survival has not been reached. CONCLUSION: Total skin electron beam followed by allogeneic stem-cell transplantation merits additional evaluation for a selected group of patients with refractory, advanced, cutaneous T-cell lymphoma with evidence for graft-versus-tumor effect.

Palliative total skin electron beam therapy (TSEBT) for advanced cutaneous T-cell lymphoma.

Our aim was to analyze the effectiveness of palliative total skin electron beam therapy (TSEBT) in the management of advanced cutaneous T-cell non-Hodgkin's lymphoma (CTCL). Eighteen patients (median age 59 years) with advanced and therapy-refractory CTCL in stages IIB-IV were treated with TSEBT for the first time. The most common histological subtype was Mycosis fungoides (72%). All patients suffered from lymphoma-associated symptoms. Median daily fractions of 1 Gy were administered up to a median total dose of 25 Gy. The median follow-up period was 11 months. Nine patients (50%) achieved a complete response and seven patients (39%) had a limited response. The actuarial one-year progression-free survival was 24%. Four patients (22%) had continuing remission over a median period of six months. Lymphoma associated symptoms were improved in 16 patients (89%). The median overall survival after receiving TSEBT was 12 months, resulting in an actuarial one-year overall survival of 48%. Treatment related acute effects (grade 1 or 2) were observed in all patients during radiation therapy. Transient grade 3 epitheliolyses developed in five patients (28%), late skin effects (grade 1 and 2) in 16 patients (89%), and hypohidrosis was seen in six patients (33%). We conclude that TSEBT is a very efficient and tolerable palliative treatment for patients with advanced CTCL.

Total skin electron beam therapy may be associated with improvement of peripheral blood disease in Sézary syndrome.

Total skin electron beam radiation is an effective therapy for palliation of the cutaneous symptoms of the most common types of cutaneous T-cell lymphomas, mycosis fungoides and Sézary syndrome. We report 4 cases of patients with Sézary syndrome who had significant improvement in their blood burden of malignant cells in addition to complete cutaneous responses to total skin electron beam therapy. The data from these 4 patients illustrate the potential for total skin electron beam to be used as both a skin and blood tumor debulking agent, and not merely as a palliation for skin symptoms.

Cutaneous lymphomas.

The skin is the most common site of extranodal non-Hodgkin lymphoma, with a yearly incidence approaching 1 per 100,000 individuals in the United States. Skin lymphomas are classified broadly into cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma (CBCL). Within these broad categories, multiple unique pathologic entities exist with a wide array of natural histories and treatment options. Radiotherapy plays an important role in the curative treatment of localized CTCL and CBCL and may be used to palliate cutaneous and visceral symptoms associated with advanced disease. This review highlights the role of radiotherapy in the multidisciplinary management of cutaneous lymphoma.

Leukoderma associated with Sézary syndrome: a rare presentation.

We describe a patient with Sézary syndrome who was initially seen with the rare occurrence of both generalized erythroderma and extensive leukoderma of his lower limbs. Apart from the absence of melanocytes in the leukodermic skin, histopathologic features of both areas were identical, showing an infiltrate of atypical lymphocytes with epidermotropism. This form of Sézary syndrome-associated leukoderma is clinically distinguishable from hypopigmented mycosis fungoides in which hypopigmented lesions are the sole manifestation of the cutaneous T-cell lymphoma.

Total skin electron beam therapy in mycosis fungoides. Our experience from 1985 to 1999.

PURPOSE: The specific goal of this retrospective study is to evaluate the role of total skin electron beam therapy (TSEBT) in the treatment of Mycosis Fungoides (MF) and to assess the most significant prognostic factors in univariate and multivariate analyses. MATERIAL AND METHODS: From January 1985 to December 1999, 92 TSEBT (Stanford Standing technique) were performed on a total of 86 patients (63 with Mycosis Fungoides, 6 with Sezary Syndrome and 17 with Cutaneous Lymphomas). This study considers only the Mycosis Fungoides group, which consisted of 60 cases evaluable for response, survival and toxicity. The distribution of patients by stage (MFCG Staging Classification, 1991) was 21, 5, 12, 22 for stages I, II, III and IV, respectively. RESULTS: The overall response rate was 96.6% (58/60) with complete response (CR) in 50/60 patients (83.3%) and partial response (PR) in 8 cases (13.3%). The five-year and ten-year actuarial overall survival (OS) was 50% and 45%, respectively. Local control, intended as control of the disease in the skin, was 35% at five years and 20% at ten years, and was correlated with skin involvement. The prognostic factors confirmed by the multivariate analysis for both overall survival and local control were: T (p<0.001) and response after TSEBT (p<0.001). The treatment was very well tolerated. CONCLUSIONS: Our study showed good results in terms of response and survival with a long follow-up time (mean value 40 months). We confirm that TSEBT yields very good results in early-stage MF; additional trials of combined modality and investigational therapies are needed to improve the outcome for advanced-stage disease.

Total skin electron radiation for patients with erythrodermic cutaneous T-cell lymphoma (mycosis fungoides and the Sézary syndrome).

BACKGROUND: There is limited published evidence regarding the efficacy of total skin electron beam radiation for patients with the diffuse erythrodermic form of mycosis fungoides. METHODS: Forty-five patients with erythrodermic mycosis fungoides were managed at McMaster University in Hamilton, Ontario, Canada (n=34), and at Yale University (n=11) between 1970 and 1996. All received radiation without neoadjuvant, concomitant, or adjuvant therapies. The median age was 67 years (range, 42-84 years). The male-to-female ratio was 2.2. Fifteen received radiation for the treatment of newly diagnosed disease. There were 28 with Stage III (T4 N0-1 M0), 13 with Stage IVA (T4 N2-3 M0), and 4 with Stage IVB (T4 N0-3 M1) disease, and 21 had blood involvement. The median radiation dose was 32 gray (Gy) (range, 4.8-40 Gy). The median treatment time was 21 days (range, 3-125 days). A technically more intense method of radiation (32-40 Gy and 4-6 MeV electrons) was administered to 23 patients. RESULTS: All patients responded. The rate of complete cutaneous remission was 60%, with 26% remaining progression free at 5 years. Remission was associated with more intense radiation (P=0.014 in multivariate analysis with adjustment for blood and staging information). With the more intense radiation, 74% attained remission, with 36% remaining progression free at 5 years. For 8 patients with Stage III disease without blood involvement, all entered remission, with 69% remaining progression free at 5 years. Twenty of 30 deaths were related to mycosis fungoides. The median overall survival was 3.4 years, with a 10-year estimate of 28%. The median cause specific survival was 5 years, with a 10-year estimate of 43%. Both overall and cause specific survival were associated with an absence of blood involvement (both P<0.03 in multivariate analysis). Age was not a significant factor. Toxicities of radiation were acceptable when radiation was administered over 6-9 weeks at 5 fractions per week. CONCLUSIONS: Total skin radiation is an efficient monotherapy for patients with erythrodermic mycosis fungoides. With more intense radiation, the rate of cutaneous remission is 74%, and 27% remain progression free at 10 years. Radiation may be most efficacious in Stage III, with no blood involvement. When there is blood, lymph node, or visceral involvement, combined modality therapies should be explored.

Electron beam treatment for cutaneous T-cell lymphoma.

Total skin electron radiation has proven efficacy in treating MF. It is a complex technique that requires a dedicated radiation team, involving physicists, radiotherapists, and radiation oncologists. A center must treat a sufficiently high volume of patients to justify the development of TSE, with appropriate organization, time, and expense. The radiation team should be an integral part of a multidisciplinary clinical group, including medical oncologists, dermatologists, pathologists, and nurses. In these contexts, TSE has appropriately been developed in a limited number of centers. Cooperation between these centers is essential for further refinement of TSE techniques and for evolution of the role of TSE in the management of most patients with MF.

Chemotherapy for mycosis fungoides and the Sézary syndrome.

Although conventional cytotoxic chemotherapy agents used alone or in combination have demonstrated activity in MF/SS, there are no studies that clearly demonstrate improvement in survival of treated patients. Newer compounds worthy of further clinical investigation in these patients include temazolamide, an alkylating agent with activity in brain neoplasms, the taxanes, and topoisomerase inhibitors, including topotecan and CPT-11. In addition, the combination of cytotoxic chemotherapies with biologic modalities, such as targeted toxins and immunomodulatory agents, has yet to be explored.