Mogamulizumab and Concomitant Hypofractionated Low-Dose Total Skin Electron Beam Therapy (2 × 4 Gy) in Cutaneous T-Cell Lymphoma: Proof of Principle, Report of Two Cases.

Patients with advanced-stage mycosis fungoides (MF IIB-IVB) and Sézary syndrome (SS) have poor prognoses, with survival ranging from 4.7 to 1.4 years depending on the disease stage. There is a need for therapeutic approaches that lead to long-lasting responses and improved quality of life and survival. Mogamulizumab, a humanized antibody against the CCR4 molecule, and low-dose total skin electron beam therapy (TSEBT) are two known established treatments for MF and SS as a monotherapy. However, little is known about the potential additive effect on the combination of both treatments. We report here for the first time the concurrent use of low-dose hypofractionated TSEBT (2 × 4 Gy) with mogamulizumab. Based on two relapsed/refractory and advanced-stage CTCL patients, we show that this combination may be well tolerated in advanced-stage MF or SS and may potentially lead to an additive treatment effect on response times, particularly in the skin and blood within two weeks. We propose that this combination may be a treatment option for patients with SS. Further research is needed to understand the efficacy and tolerability profile of this therapeutic combination and to determine if there is an additive effect of the combination on the response rates when compared with the monotherapy.

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023.

On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS.

A simple solution to create a custom scalp-sparing helmet to prevent alopecia in patients undergoing total skin electron beam therapy for cutaneous T cell lymphoma.

Total skin electron beam therapy (TSEBT) is effective for patients with refractory or diffuse skin involvement of cutaneous T cell lymphomas (CTCL). A common concern for patients undergoing TSEBT is the development of alopecia. Patients are already burdened with the physical symptoms associated with their disease; therefore, mitigating additional physical side effects of treatment, including cosmetic concerns, is important. As such, the purpose of this study is to evaluate a novel technique to prevent alopecia after TSEBT. Prior scalp sparing techniques have relied largely on materials found in the radiation department (e.g., lead, Superflab bolus), but in this report, we utilized a custom blue wax polyethylene material to create a custom scalp-sparing, dose attenuating, helmet. The priorities that lead to investigating this solution included patient comfort, full scalp protection, and practicality. We wanted to find a light weight, snug fitting, helmet to protect the entire hair line, that could be easily fabricated for any patient. In the end, we found success in our efforts to minimize radiation to the scalp for indistinguishable hair volume changes.

Short-term efficacy and safety of total skin electron beam therapy in mycosis fungoides: Systematic review and meta-analysis.

Total skin electron beam therapy (TSEBT) is one of the mainstays of treatment for mycosis fungoides. The most common modalities are standard dose (30-36 Gy) and low dose (10-12 Gy). To review the literature on the efficacy and safety profiles of standard dose and low dose TSEBT. We searched electronic databases for studies that enrolled patients with Mycosis Fungoides and treated with TSEBT. We estimated the event rates associated with low dose and standard dose TSEBT. The Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guideline was followed. Main outcomes were complete response rate, partial response rate, mild and severe adverse events rate low dose TSEBT had a Complete Response Rate of 28% [0.19, 0.37], an Overall Response Rate of 85% [0.76, 0.93], a mild adverse events rate of 93% [0.82, 1.04] and a severe adverse events rate of 5% [-0.04; 0.14] Standard dose TSEBT had a Complete Response Rate of 57% [0.41; 0.73], the Overall Response Rate was 99% [0.97; 1.02], the mild adverse events rate was 100%, the severe adverse events rate was 7% [-0.01; 0.16]. Comparing standard dose TSEBT in the early versus advanced stages, advanced stages patients had a Risk Ratio = 0.77 in obtaining a Complete Response [0.64, 0.92](p = 0.0158). TSEBT is an associated with an excellent short term safety profile. Both schedules show high ORR, with standard dose TSEBT demonstrating highest CRR. Advanced stage of disease negatively influence the CRR.

[Radiotherapy for cutaneous lymphomas]. / Radiotherapie kutaner Lymphome.

BACKGROUND: Primary cutaneous lymphomas (CL) are highly radiosensitive. Therefore, radiotherapy is an integral part of multimodality treatment. AIM: The present work provides an overview of indications, technical developments, and dose concepts for total skin electron beam therapy (TSEBT), local radiotherapy as well as maintenance therapy, and current combination studies regarding cutaneous T­ and B­cell lymphomas. MATERIALS AND METHODS: We performed a selective literature search in the PubMed database on the topic of radiotherapy for CL and a search for current studies using clinicaltrials.gov. Furthermore, we describe our own treatment strategies and summarize national and international guidelines. RESULTS: Low-dose TSEBT is nationally and internationally recommended as an alternative to conventional 36 Gy TSEBT. The main advantages are better tolerability, the possibility of retreatment, a shorter treatment course (approximately 3 weeks), and a short time to response. In current studies, TSEBT is usually delivered to a total dose of 12 Gy and combined with immunotherapy and epigenetic therapy. Local radiotherapy is indicated for mycosis fungoides (MF) tumors and is a curative treatment regimen for other CL, particularly primary cutaneous B­cell lymphomas. CONCLUSION: TSEBT is a very effective treatment for MF and is a highly effective palliative treatment, leading to rapid symptom relief and improvement in quality of life. It is an important treatment option, especially in patients with extensive generalized lesions or advanced tumor stage. Local radiation is used as part of TSEBT for tumors and as a boost to undertreated areas. Other CLs are primarily curable with local radiotherapy.

Total skin electron beam therapy (TSEBT) in management of mycosis fungoides: A case series.

A retrospective review was conducted In Aga Khan University from January 2013-December 2020 for patients who received Total Skin Electron Beam Therapy (TSEBT) on the management of Mycosis Fungoides (MF). The clinical response rate and disease-free interval (DFI) was evaluated for three patients. All of the patients received a 3600 cGy dose of radiation. Clinical complete remission (cCR) was observed in two out of three patients, while one patient showed clinical partial response. Following the cCR to TSEBT, the DFI of the first patient with stage 1B lasted 30 months, while the second patient with stage IIB remained disease free for five months. TSEBT is an effective treatment for MF disease. It can thus be expected that patients with limited disease in the early stage can acquire a cCR with a longer DFI. The clinical outcomes of our study show concordance with the literature. The patients who had extensive (T3) skin involvement and had refractory diseases showed lower DFI with radiation.

Changes in total skin electron beam therapy modalities for mycosis fungoides: A single-centre study.

BACKGROUND: Mycosis fungoides (MF) is a highly radiosensitive disease. Total skin electron beam therapy (TSEBT) is an effective option that may allow prolonged response for several months. Recently, a low-dose regimen (12 Gy) has been reported more frequently, with less complete response than for standard doses (36 Gy) but better safety. Our aim was to compare patients treated with 12-Gy and 36-40-Gy TSEBT regimens at our centre for efficacy and safety. METHODS: This retrospective, monocentric study in Bordeaux University Hospital included all MF patients treated with 12-Gy or 36-40-Gy TSEBT between 2011 and 2020. RESULTS: Patients presented with MF at the following stages: 15 T2, including 9 folliculotropic MF; 2 T3, including 1 folliculotropic; 8 T4, including 2 Sézary syndromes. The mean follow-up time after TSEBT was 43.5 months [range: 2-128] for the 36-40-Gy group and 25.2 months [range: 4-45] for the 12-Gy group. The 3-month overall response rate (ORR) was similar for both groups (84.6% for 36-40 Gy and 91.7% for 12 Gy), but there was a tendency to more complete response in the 36-40-Gy group (30.8% vs 8.3%, P=0.35). Progression-free survival (PFS) tended to be better in the 36-40-Gy group than in the low-dose group (15.7 months vs 5.3 months; P=0.28). Patients treated with low-dose TSEBT had a lower incidence of radiation dermatitis (16.7% vs 38.4%, P=0.42). CONCLUSION: We confirm that TSEBT is an effective option, including at lower doses. Differences between low- and standard-dose regimens were not significant in our series. Although a low-dose regimen seemed to result in lower complete response and long-term efficacy rates in comparison with a standard dose, treatment at lower doses presents the advantage of repeatability, with fewer and weaker side effects, in the event of disease recurrence. Second-line treatments were mostly skin-directed in this group.

Total skin electron beam therapy for cutaneous T-cell lymphomas in the Netherlands: A retrospective analysis of treatment outcomes and selection for high or low dose schedule.

PURPOSE: Total skin electron beam therapy (TSEBT) is used mostly in the treatment of cutaneous T cell lymphoma. In this study we describe the results of TSEBT applied in the Netherlands using two different schedules, a conventional dose schedule of 35 Gy and a low-dose schedule of 12 Gy. We aimed to evaluate the treatment results in and compare treatment outcomes between the two treatment groups and to further define indications for both doses. METHODS: In the LUMC, Leiden, we performed a retrospective analysis of 51 patients treated with TSEBT between January 2008 and December 2018, with follow-up untill December 2019. Thirty one patients were treated with 35 Gy and twenty with 12 Gy. The dose was chosen based on the severity of skin involvement. Outcome measures were time to meaningful progression, survival, response rate and toxicity. RESULTS: Time to meaningful progression was 5.1 months with no significant differences between dose groups (P = 0.77). Overall survival was 27.4 months. Both time to progression and survival were significantly better for T2 vs T3 stage. Overall response rate was 80.4 %. Both dose groups showed improvement of symptoms. Treatment was generally well tolerated. CONCLUSIONS: Both high-dose and low-dose TSEBT offer similar results for TMP and OS. It remains unclear which patients benefit most from a high-dose schedule. We propose to use the low-dose schedule as a standard for TSEBT and use supplementary boosts or escalation to high-dose treatment for patients unresponsive to the low-dose schedule.

In vivo Dosimetry for Dose Verification of Total Skin Electron Beam Therapy Using Gafchromic® EBT3 Film Dosimetry.

Background and Purpose: Total skin electron beam therapy (TSEBT) is an important skin-directed radiotherapeutic procedure done in the treatment of cutaneous T-cell lymphomas, namely, mycosis fungoides (MF). This procedure is usually done at larger source-to-surface distances with the patient standing on a rotatory platform. As the patient has to stand in different positions without any rigid immobilization devices, there are chances that the total skin may not get uniformly irradiated which could lead to nonuniform dose distributions. Therefore, all the necessary arrangements should be made to evaluate the dose for different regions of the skin using suitable in vivo dosimeters at the radiotherapy centers offering these treatments. This study aimed to evaluate the consistency between the delivered and planned doses in vivo during TSEBT using Gafchromic EBT3 film dosimetry. Materials and Methods: The surface dose for the six MF patients treated for TSEBT at our hospital from 2018 to 2022 was measured and evaluated. 2 cm × 2 cm Gafchromic® EBT3 films were used to measure skin dose at reference body positions of clinical interest. All the patients were treated with the modified Stanford technique. The irradiated film strips were analyzed for the dose using the IMRT OmniPro software. The doses at respective positions were expressed as mean dose ± standard deviation and the deviation was calculated as the percentage of the prescribed dose. Results: One hundred and fifty-four Gafchromic® EBT3 film strips irradiated on six TSEBT patients showed a maximum dose variation of 2.00 ± 0.14 Gy, in the central body regions. The dose variation in the peripheral areas such as hands and ears was larger. A variation of 2 ± 0.32 Gy was observed on the hands and ears. The uniformity of the dose delivered to maximum body parts was within -7% and +16% for the peripheral areas like hands. The American Association of Physicists in Medicine recommends a dose uniformity of 8% and 4% in the vertical and horizontal patient plane for direct incident beam; however, for oblique incidences like in the modified Stanford technique, the dose variation is about 15%. Conclusion: In vivo dosimetry using Gafchromic EBT3 film dosimetry for TSEBT yields objective data to find the under or overdose regions. That can be useful to provide quality treatment, especially when treatments tend to be as complex as TSEBT.

Sweeping-beam technique with electrons for large treatment areas as total skin irradiation : Dosimetric and technical aspects of a modified Stanford technique.

PURPOSE: Total skin electron beam therapy (TSEBT) is still a technical and therapeutic challenge today. Thus, we developed TSEBT using a sweeping-beam technique. METHODS: For treatment delivery, a linear accelerator Versa HD (ELEKTA, Stockholm, Sweden) with high-dose-rate electrons (HDRE) was used with a dose rate of 9000 MU/min. Dosimetry quality assurance was performed by multiple measurements with film dosimetry, 2D array, and Roos chamber. RESULTS: Clinical experience shows that treatment durations of 75 to 90 min are usual for the Stanford technique without using HDRE. With this new sweeping-beam irradiation technique, the total treatment time of a daily fraction could be reduced to 20 min while keeping over- and underdosing low. The treatment area is about 60 cmâ€¯× 200 cm and the dose distribution is uniform within 2% and 5% in vertical and horizontal directions, respectively. Initially, the electron energy of 6 MeV is reduced to 3.2 MeV by 1­cm polymethylmethacrylat (PMMA) scatter and the irradiation conditions of a source-surface distance (SSD) of 350 cm. The photon contamination drops to under 1%. CONCLUSION: These results show that the mean dose to total skin varies between 1.3 and 1.8 Gy. The sweeping-beam technique with electrons has a homogeneous dose distribution in connection with a short treatment time.

Total skin electron beam therapy for primary cutaneous T-cell lymphomas: clinical characteristics and outcomes in a Mexican reference center.

AIM: The aim of this study was to assess treatment modalities, treatment response, toxicity profile, disease progression and outcomes in 14 patients with a confirmed diagnosis of primary cutaneous T-cell lymphoma (PCTCL) treated with total skin electron beam therapy (TSEBT). BACKGROUND: Primary cutaneous lymphomas (PCLs) are extranodal non-Hodgkin lymphomas originating in the skin without evidence of extracutaneous disease at diagnosis. Despite advances in systemic and local therapy options, the management of advanced stages remains mostly palliative. MATERIALS AND METHODS: This is a retrospective study of patients with PCTCL, diagnosed and treated in a reference center in Mexico City, analyzing treatment modalities, response to treatment, long-term outcome, and mortality. RESULTS: Eight males (57%) and 6 (43%) females were identified. Most patients were stage IVA (n = 5, 36%) followed by stage IB and IIB (28.5% and 21.4%, respectively). Eleven patients received the low-dose RT scheme (12 Gy), 1 patient, the intermediate-dose RT scheme (24 Gy), and 2 patients, the conventional-dose RT scheme (36 Gy). Mean follow-up time was 4.6 years. At first follow-up examination, 6-8 weeks after radiotherapy, the overall response rate (ORR) for the cohort was 85%. The median PFS for the whole cohort was 6 months. CONCLUSION: This study reinforces the role of TSEBT when compared with other treatment modalities and novel agents. Low-dose TSEBT is now widely used because of the opportunity for retreatment.

Low dose total skin electron beam therapy for the management of T cell cutaneous lymphomas.

Mycosis fungoides (MF) represent the most common type of primary cutaneous lymphomas. Total skin electron beam (TSEB) therapy to a total skin administered dose of 36 Gy represents a very effective treatment regimen and its role in the management of MF is well established. Unfortunately, the issue in MF is that despite the proved effectiveness of radiation therapy, disease regress, and the main goal of TSEB treatment seems to be the prolongation of the overall response duration time. Taking into consideration the high radio-sensitivity of the disease, lower radiation doses have been tested with acceptable and comparable results. We prospectively analyzed low dose TSEB in 14 patients treated at ATTIKON University Hospital from 2011 to 2017. After a median duration of follow up time of 39 months we found that low dose TSEB is an effective treatment option, since therapeutic results are more than acceptable, with minimal toxicity. The fact that it can be repeated safely in the natural course of a "regressive" disease makes it more attractive than the standard full dose scheme of 36 Gy.

A prospective cohort study of condensed low-dose total skin electron beam therapy for mycosis fungoides: Reduction of disease burden and improvement in quality of life.

BACKGROUND: Low-dose total skin electron beam therapy (TSEBT) for mycosis fungoides is popular because of reduced toxicity with effective palliation. We condensed TSEBT, reducing visits by half and overall treatment length by one third. OBJECTIVE: To determine the efficacy and safety of a novel condensed low-dose TSEBT for mycosis fungoides. METHODS: We conducted a cohort study (2014-2018) with a median follow-up of 22.8 months. We delivered 12 Gy per 6 fractions with the modified Stanford technique, 3 fractions per week, with boosts to shadowed sites at risk between treatments, completing in 2 weeks. Primary outcomes included clinical response, duration of and time to response, and toxicity. Secondary outcomes included patient-reported quality of life (pain, pruritus, and Dermatology Life Quality Index) and physician-scored disease burden (body surface area involvement and Modified Skin Weighted Assessment Tool). RESULTS: Of 25 patients, stage IB was most common at the time of TSEBT (36%). The overall response rate was 88%. Most common was a near complete response (36%), and complete response was achieved in 6 (24%) patients. The median duration of response was 17.5 months (3.5-44.2), and the median time to response was 2 months (range, 0.9-4.1). No patients had toxicity of grade 3 or greater. QOL and disease burden showed significant benefit after TSEBT (P < .001). LIMITATIONS: Cohort study with limited sample size. CONCLUSIONS: Condensed, low-dose TSEBT has favorable outcomes and toxicity with logistical convenience.

Monte Carlo investigation of the effect of skin tissue optical properties on detected Cherenkov emission.

In this study, we use Monte Carlo modelling to investigate the effect of tissue optical properties on Cherenkov emission detected from tissue surface. MC simulations are performed for wavelength between 400-1000nm and the values of absorption coefficient at each wavelength are determined based on the molar extinction coefficients of oxy- and deoxy-hemoglobin, with varying total haemoglobin concentration and tissue oxygen saturation of 70%. Tissue reduced scattering coefficient is approximated using µs'(λ) = Aλ-0.838. A range of clinically relevant tissue optical properties was investigated, with absorption coefficient between 0.1 and 1 cm-1 and reduced scattering coefficient between 5 and 40 cm-1 at 665nm. The angular distribution, depth of origins and the effect of tissue optical properties on Cherenkov emission on tissue surface are evaluated.

Dosimetric evaluation of electron total skin irradiation using gafchromic film and thermoluminescent dosimetry.

AIM OF STUDY: The aim of this study is to evaluate some dosimetry parameters such as uniformity, surface dose, and max depth dose with thermoluminescent dosimetry (TLD) and EBT3 film in total skin electron beam therapy (TSEBT). METHODS: Stationary and rotary methods were set on Varian linear accelerator, Clinac 2100C. To create a radiation field large enough (168 cm × 60 cm) and uniform, the source skin distance was set 400 cm. Electron beam energy was 6 MeV. The skin dose values were obtained in 21 different points on the phantom surface. RESULTS: The results of dose uniformity in stationary technique were obtained as 10% and 2.6% by TLDs and 6% and 2.3% by films in longitudinal axis and transverse axis, respectively. The measurements at rotational technique by TLDs at the referred conditions showed a homogeneous total field with intensity variation of 10% in the longitudinal axis and 4% at horizontal axis. CONCLUSION: Based on the results of this study, stationary techniques are preferred for TSEBT. The main advantage of rotational techniques is reducing the time of treatment. The results also demonstrate that TLD should be routinely used in TSEBT treatment. Due to the high sensitivity of radiochromic films, this type of film was suitable for a wide therapeutic field. Comprehensive treatment to Rando phantom showed that the uniformity is better at the trunk than in the mobile parts of the body; the soles of the feet, perineum region, and scalp vertex should be treated in boost.

Simultaneous integrated boost with helical arc radiotherapy of total skin (HEARTS) to treat cutaneous manifestations of advanced, therapy-refractory cutaneous lymphoma and leukemia - dosimetry comparison of different regimens and clinical application.

BACKGROUND: Helical irradiation of the total skin (HITS) was modified as simultaneous integrated boost (SIB)-helical arc radiotherapy of total skin (HEARTS) technique and applied to an acute myeloid leukemia (AML) patient with disseminated leukemia cutis. METHODS: The original HITS plan was revised for different regimens, i.e. HEARTS, low-dose HEARTS and SIB-HEARTS. The uniformity index (UI), conformity index (CI), and dose of organs at risk (OARs) were used to evaluate the plans. Additionally, the SIB-HEART (21/15 Gy) was delivered to the total skin and chloromas. RESULTS: No significant differences were observed for the CI and UI between HITS and HEARTS regimens. Compared with HITS, the reduced mean doses to various bone marrows ranged from 17 to 88%. The mean OARs doses for the head, chest and abdomen of a patient with AML treated with SIB-HEARTS (21/15 Gy) were 2.1 to 21.9 Gy, 1.8 to 7.8 Gy and 1.7 to 3.3 Gy, respectively. No severe adverse effects were noted except for grade 4 leukocytopenia and thrombocytopenia. CONCLUSION: HEARTS and different regimens reduced the dose to OARs and bone marrow while maintaining the uniformity and conformity. SIB-HEARTS deliveries different doses to the total skin and enlarged tumors simultaneously. TRIAL REGISTRATION: Retrospectively registered and approved by the Institutional Review Board of our hospital ( FEMH-106151-C ).