Knowledge and competences in hematological malignancies amongst radiation oncology residents in Germany-results from a national survey.

INTRODUCTION: Radiation oncology is a pivotal modality in the treatment of hematologic malignancies. To enable state-of-the-art patient care, structured education during residency is essential. However, given the lack of detailed data, the scope of educational opportunities available to trainees remains elusive. This prompted our group to perform a national survey amongst radiation oncology residents in Germany assessing the status quo of competences in the treatment of lymphoma and leukemia patients. Furthermore, areas of potential improvement were identified to further the goal of competence-based education for residents. METHODS: A survey-based analysis was conducted to assess the knowledge and competence of radiation oncology residents in Germany regarding hematological malignancies. A decisive questionnaire covering demographics, self-assessment of competences, and areas for improvement was developed in adaption of a survey by the Association of Residents in Radiation Oncology and distributed amongst 1439 members of the German Society of Radiation Oncology. Responses were collected anonymously via an online survey tool and analyzed using descriptive statistics and chi-square tests. RESULTS: A total of 59 complete and 22 partial responses were collected, yielding a 5.6% response rate. Participants' competence varied, with notable experience gaps in pediatric cases, proton therapy, and large-field techniques like total-skin irradiation or pediatric total body irradiation. While participants felt confident in treatment planning and patient counseling, they showed deficiencies in the definition of the planning target volume for modern involved site radiotherapy. Resources for education included national and international guidelines, scientific reviews, and textbooks. Board-certified radiation oncologists and physicians from specialized lymphoma centers demonstrated higher overall competence levels. CONCLUSION: This survey highlights the diversity of resident education regarding hematological malignancies in German radiation oncology programs. Knowledge gaps exist in key areas, including pediatric cases and specialized techniques. Competence-based education, interactive teaching formats, and rotations to specialized centers are potential strategies to address these gaps. The study contributes to the understanding of the federal educational landscape, underscoring the need for standardized and comprehensive training to ensure optimal patient care in hematological malignancies within the context of radiation oncology. Further research and collaborations are warranted to enhance training and expertise in this critical domain.

Sulfonamides as anticancer agents: A brief review on sulfonamide derivatives as inhibitors of various proteins overexpressed in cancer.

Sulfonamides have gained prominence as versatile agents in cancer therapy, effectively targeting a spectrum of cancer-associated enzymes. This review provides an extensive exploration of their multifaceted roles in cancer biology. Sulfonamides exhibit adaptability by acting as tyrosine kinase inhibitors, disrupting pivotal signaling pathways in cancer progression. Moreover, they disrupt pH regulation mechanisms in cancer cells as carbonic anhydrase inhibitors, inhibiting growth, and survival. Sulfonamides also serve as aromatase inhibitors, interfering with estrogen synthesis in hormone-driven cancers. Inhibition of matrix metalloproteinases presents an opportunity to impede cancer cell invasion and metastasis. Additionally, their emerging role as histone deacetylase inhibitors offers promising prospects in epigenetic-based cancer therapies. These diverse roles underscore sulfonamides as invaluable tools for innovative anti-cancer treatments, warranting further exploration for enhanced clinical applications and patient outcomes.

The evolving role of reduced-dose total skin electron beam therapy in skin malignancies: the renaissance of a rare indication.

Definitive radiation therapy is an effective local treatment for several cutaneous malignancies. Patients with diffuse or generalized skin manifestations might require total skin electron beam therapy (TSEBT) as an alternative treatment to the chasing technique. In this short communication, we highlight the evolving role of TSEBT and present its role in various forms of skin malignancies.

Reduction of tumor volume during radiotherapy in patients with small-cell lung cancer and its prognostic significance.

BACKGROUND: Several studies have reported the potential prognostic significance of tumor volume reduction ratio (VRR) induced by radiotherapy (RT) in patients with non-small-cell lung cancer. However, there are no data yet on the prognostic significance of volumetric shrinkage in patients with small-cell lung cancer (SCLC). This study aimed to demonstrate the correlation between tumor volume reduction ratio and treatment outcomes. MATERIALS AND METHODS: The study included 61 patients with SCLC treated with fractionated RT of the primary tumor at our institution between 2013 and 2020. The relationship between volumetric changes in gross tumor volume (GTV) during radiotherapy and outcomes were analyzed and reported. RESULTS: The median radiation dose was 59.4 Gy (median fraction dose was 1.8 Gy). The median GTV before radiotherapy was 74 cm3, with a median GTV reduction of 48%. There was a higher VRR in patients receiving concurrent radiochemotherapy (p = 0.05). No volumetric parameters were identified as relevant predictors of outcome in the entire cohort. In multivariate analysis, only age had an impact on survival, while prophylactic whole-brain radiation influenced the progression-free survival significantly. CONCLUSION: Concurrent chemotherapy was associated with a higher VRR than sequential chemotherapy. No significant impact of VRR on patients' outcome or survival was detected.

Impact of dose escalation on colostomy-free survival and treatment outcome in squamous cell anal carcinoma.

PURPOSE: Primary radiochemotherapy (RCT) constitutes the standard of care for early- and advanced-stage anal carcinoma. This retrospective study investigates the impact of dose escalation on colostomy-free survival (CFS), overall survival (OS), locoregional control (LRC), progression-free survival (PFS), and acute and late toxicities in patients with squamous cell anal cancer. METHODS: Considered were the outcomes of 87 patients with anal cancer treated with radiation/RCT between May 2004 and January 2020 at our institution. Toxicities were evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE version 5.0). RESULTS: The 87 patients received treatment with a median boost of 63 Gy to the primary tumor. With a median follow-up of 32 months, the 3­year CFS, OS, LRC, and PFS were 79.5%, 71.4%, 83.9%, and 78.5%, respectively. Tumor relapse occurred in 13 patients (14.9%). Dose escalation to > 63 Gy (maximum 66.6 Gy) to the primary tumor in 38/87 patients revealed a nonsignificant trend for improved 3­year CFS (82.4% vs. 97%, P = 0.092), a significantly improved CFS for T2/T3 tumors (72.6% vs. 100%, P = 0.008), and a significantly improved 3­year PFS for T1/T2 tumors (76.7% vs. 100%, P = 0.035). While acute toxicities did not differ, dose escalation > 63 Gy led to a higher rate of chronic skin toxicities (43.8% vs. 69%, P = 0.042). Treatment with intensity-modulated radiotherapy (IMRT) showed a significant improvement in 3­year OS (75.4% vs. 53.8%, P = 0.048). In multivariate analysis, significant improvements for T1/T2 tumors (CFS, OS, LRC, PFS), G1/2 tumors (PFS), and IMRT (OS) were shown. The nonsignificant trend for CFS improvement with dose escalation > 63 Gy was also apparent in multivariate analysis (P = 0.067). CONCLUSION: Dose escalation > 63 Gy (maximum 66.6 Gy) may improve CFS and PFS for certain subgroups, with a concomitant increase in chronic skin toxicities. Modern IMRT seems to be associated with an improvement in OS.

Low-dose total skin electron beam therapy plus oral bexarotene maintenance therapy for cutaneous T-cell lymphoma.

BACKGROUND: Total skin electron beam therapy (TSEBT) combined with systemic therapy or maintenance treatment is a reasonable approach to enhance the remission rate and duration in mycosis fungoides (MF) and Sézary syndrome (SS). This study assesses the efficacy of oral bexarotene therapy after low-dose TSEBT for patients with MF and SS. METHODS: In this prospective observational study, we recruited MF/SS patients for treatment with low-dose total skin electron beam therapy (TSEBT) with or without bexarotene therapy to describe outcomes and toxicities. RESULTS: Forty-six subjects with MF or SS underwent TSEBT between 2016 and 2021 at our institute. Following TSEBT, 27 patients (59 %) received oral bexarotene treatment. The median follow-up was 13 months. The overall response rate (ORR) for the cohort was 85 %. The response rate was significantly higher with combined modality (CM) than TSEBT alone (96 % vs. 68 %, p = 0.03). Median progression-free survival (PFS) for the CM was 17 months versus five months following TSEBT alone (p = 0.001). One patient (4 %) in the retinoid group discontinued the bexarotene therapy because of adverse events. The administration of bexarotene therapy did not increase radiation-related toxicities. CONCLUSIONS: Response rate and progression-free survival might be improved with TSEBT in combination with oral bexarotene compared to TSEBT alone.

Impact of radiation techniques on lung toxicity in patients with mediastinal Hodgkin's lymphoma.

PURPOSE: Mediastinal radiotherapy (RT), especially when combined with bleomycin, may result in substantial pulmonary morbidity and mortality. The use of modern RT techniques like intensity-modulated radiotherapy (IMRT) is gaining interest to spare organs at risk. METHODS: We evaluated 27 patients who underwent RT for Hodgkin's lymphoma between 2009 and 2013 at our institution. For each patient, three different treatment plans for a 30-Gy involved-field RT (IFRT) were created (anterior-posterior-posterior-anterior setup [APPA], 5­field IMRT, and 7­field IMRT) and analyzed concerning their inherent "normal tissue complication probability" (NTCP) for pneumonitis and secondary pulmonary malignancy. RESULTS: The comparison of different radiation techniques showed a significant difference in favor of standard APPA (p < 0.01). The risk of lung toxicity was significantly higher in plans using 7­field IMRT than in plans using 5­field IMRT. The absolute juxtaposition showed an increase in risk for radiation pneumonitis of 1% for plans using 5­field IMRT over APPA according to QUANTEC (Quantitative Analyses of Normal Tissue Effects in the Clinic) parameters (Burman: 0.15%) and 2.6% when using 7­field IMRT over APPA (Burman: 0.7%) as well as 1.6% when using 7­field IMRT over 5­field IMRT (Burman: 0.6%). Further analysis showed an increase in risk for secondary pulmonary malignancies to be statistically significant (p < 0.01); mean induction probability for pulmonary malignoma was 0.1% higher in plans using 5­field IMRT than APPA and 0.19% higher in plans using 7­field IMRT than APPA as well as 0.09% higher in plans using 7­field IMRT than 5­field IMRT. During a median follow-up period of 65 months (95% confidence interval: 53.8-76.2 months), only one patient developed radiation-induced pneumonitis. No secondary pulmonary malignancies have been detected to date. CONCLUSION: Radiation-induced lung toxicity is rare after treatment for Hodgkin lymphoma but may be influenced significantly by the RT technique used. In this study, APPA RT plans demonstrated a decrease in potential radiation pneumonitis and pulmonary malignancies. Biological planning using NTCP may have the potential to define personalized RT strategies.

A novel approach to SBRT patient quality assurance using EPID-based real-time transit dosimetry : A step to QA with in vivo EPID dosimetry.

PURPOSE: Intra- and inter-fraction organ motion is a major concern in stereotactic body radiation therapy (SBRT). It may cause substantial differences between the planned and delivered dose distribution. Such delivery errors may lead to medical harm and reduce life expectancy for patients. The project presented here investigates and improves a rapid method to detect such errors by performing online dose verification through the analysis of electronic portal imaging device (EPID) images. METHODS: To validate the method, a respiratory phantom with inhomogeneous insert was examined under various scenarios: no-error and error-simulated measurements. Simulation of respiratory motions was practiced for target ranges up to 2 cm. Three types of treatment planning technique - 3DCRT (three-dimensional conformal radiation therapy), IMRT (intensity modulated radiation therapy), and VMAT (volumetric modulated arc therapy - were generated for lung SBRT. A total of 54 plans were generated to assess the influence of techniques on the performance of portal dose images. Subsequently, EPID images of 52 SBRT patients were verified. Both for phantom and patient cases, dose distributions were compared using the gamma index method according to analysis protocols in the target volume. RESULTS: The comparison of error-introduced EPID-measured images to reference images showed no significant differences with 3%/3 mm gamma evaluation, though target coverage was strongly underestimated. Gamma tolerance of 2%/2 mm reported noticeable detection in EPID sensitivity for simulated errors in 3DCRT and IMRT techniques. The passing rates for 3DCRT, IMRT, and VMAT with 1%/1 mm in open field were 84.86%, 92.91%, and 98.75%, and by considering MLC-CIAO + 1 cm (threshold 5%), were 68.25%, 83.19%, and 95.29%, respectively. CONCLUSION: This study demonstrates the feasibility of EPID for detecting the interplay effects. We recommend using thin computed tomography slices and adding sufficient tumor margin in order to limit the dosimetric organ motion in hypofractionated irradiation with preserved plan quality. In the presence of respiratory and gastrointestinal motion, tighter criteria and consequently using local gamma evaluation should be considered, especially for VMAT. This methodology offers a substantial step forward in in vivo dosimetry and the potential to distinguish errors depending on the gamma tolerances. Thus, the approach/prototype provides a fast and easy quality assurance procedure for treatment delivery verification.

De-escalated radiotherapy for indolent primary cutaneous B-cell lymphoma.

OBJECTIVE: Radiotherapy (RT) has an established role in the curative treatment of indolent primary cutaneous B­cell lymphoma (PCBCL). With the role of low-dose regimens such as 2 × 2 Gy being uncertain, we compared conventional-dose RT to a low-dose approach and investigated outcome and toxicities. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 26 patients with 44 cutaneous lesions treated at our institution between 2007 and 2017, comprising 22 marginal zone lymphoma (PCMZL) lesions and 22 follicle center lymphoma (PCFCL) lesions. Seven lesions (16%) were treated with low-dose RT (LDRT) (4 Gy) and 37 (84%) with conventional-dose RT (≥24 Gy, median 40 Gy). Median follow-up duration was 76 months. RESULTS: The overall response rate (ORR) was 91% (complete response rate [CRR]: 75%). The 5­year local control rate (LCR) was 88% and the 10-year LCR was 84%. The response rates were significantly higher following conventional-dose RT (ORR: 92% vs. 86%; CRR: 84% vs. 29%; P = 0.007). In terms of radiation dose, the rate of infield relapses (14% vs. 11%, P = 0.4) and the 5­year LCR (86% vs. 90%, P = 0.4) were comparable in the LDRT and conventional-dose RT groups. During RT courses, about two-thirds of patients experienced mild toxicities, with grade I and II acute toxicity rates of 61% and 9%, respectively, with lower incidences of grade I (14% vs. 70%) and grade II (0% vs. 8%, P = 0.004) toxicities following LDRT. CONCLUSION: This long-term analysis confirms the excellent outcome of RT in the management of PCBCL. The LDRT concept with 4 Gy was associated with a comparable LCR and reduced rates of acute toxicity. However, the response rates were significantly lower for this group and LDRT may therefore not be recommended as standard treatment.

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.

Radiotherapy of extranodal low-grade follicular and marginal zone lymphomas: long-term follow-up of 159 patients.

OBJECTIVE: To evaluate clinical, histopathologic, and radiation (RT) dose parameters in patients with extranodal low-grade (ENLG) non-Hodgkin lymphoma (NHL) and their possible impact on local control (LC) and survival. MATERIALS AND METHODS: The medical records of 159 patients with 181 histologically confirmed ENLG-NHL lesions treated at our institution were reviewed retrospectively. RESULTS: The predominant histological subtype (73%) was marginal zone lymphoma (MZL). Common lesion sites were the gastrointestinal tract (GIT; 33%), skin (26%), and orbit (21%). The majority of patients (88%) presented with stage I/II disease. Thirty-three (20%) lesions were treated with reduced-dose RT (≤30.6 Gy) and 148 lesions (80%) with conventional-dose RT (>30.6 Gy), with an overall median dose of 39.6 Gy (range 4-63). The median follow-up period was 72 months. The 10-year local control (LC), Progression-free survival (PFS), and overall survival (OS) rates were 96, 65, and 82%, respectively. Higher overall response rate (ORR; 98% vs. 94%, p = 0.001) and complete response rate (CRR; 95% vs. 73%, p = 0.001) were observed in patients treated with conventional-dose regimens than in those treated with reduced-dose regimens. Ten-year PFS (p = 0.90) and OS (p = 0.40) was similar between the two dose groups. RT was well tolerated in both dose groups, with no grade 4/5 toxicities. In the multivariate analysis, RT dose and timing (upfront or salvage) were related to LC, whereas age, histology, and complete response (CR) to RT were associated with PFS. Patient age and radiation field size impacted OS. CONCLUSION: RT is an effective and curative local treatment for early-stage FL and MZL at conventional and reduced radiation doses. Conventional-doses seems to be associated with local response improvement, without significant differences in PFS rates. Age, histology, and response to RT may influence the PFS.

Combined total skin radiotherapy and immune checkpoint inhibitors: A promising potential treatment for mycosis fungoides and Sezary syndrome.

Radiotherapy, particularly total skin electron beam therapy (TSEB), is one of the main pillars in the strategy for treatment of cutaneous T-cell lymphoma (CTCL). Low-dose TSEB has gained considerable attention since it has a minimal toxicity profile. Low-dose TSEB has been shown to yield an overall response rate up to 95 %, although the response duration is usually short. Few studies have been published on treatment outcomes after combined treatment of CTCL with TSEB and systemic therapy. Remission rates of patients who received immune checkpoint inhibitors alone ranged from 15-38 % with a two-year progression-free survival of 69 %. Given that TSEB results in rapid reduction of the disease burden in almost all patients, we hypothesized that TSEB followed by immune checkpoint inhibitors might be a reasonable treatment with a sustained effect for treatment-experienced patients with mycosis fungoides and Sezary syndrome.

Radiotherapy for extramedullary leukaemic manifestation (Chloroma).

PURPOSE: Extramedullary leukaemic disease (EMD, synonym chloroma) is a rare solid manifestation of myeloid leukaemia for which the value of radiotherapy (RT) as a treatment strategy remains controversial. The aim of this study is to analyse the effectiveness of various RT doses for EMD in the modern treatment era. MATERIALS AND METHODS: Between January 2000 and June 2016, 20 patients with total of 45 lesions underwent RT for EMD at our institution. RESULTS: With a median radiation dose of 26 Gy (range 4-42 Gy), local remission could be achieved in 91% of patients (complete remission rate: 71%). The median duration of local control (DOLC) was 17 months (95% confidence interval [CI] 0.5-33) and the median overall survival (OS) after chloroma onset was 24 months (95% CI 11-38). No noticeable difference between high- and low-dose regimens has been observed (74% versus 68%; P = 0.5). In the multivariate analysis, only Eastern Cooperative Oncology Group (ECOG) score and bone marrow state during RT have proven to be determinant for durable local control and OS. CONCLUSIONS: Low-dose RT (≤26 Gy) achieves good local control compared to high-dose regimes. Bone marrow state during RT and ECOG score during RT may play a crucial role, influencing both DOLC and OS.

Low-dose total skin electron beam therapy for cutaneous lymphoma : Minimal risk of acute toxicities.

BACKGROUND: Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T­cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses. PATIENTS AND METHODS: We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared. RESULTS: In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P < 0.001). A lower grade 3 AE rate was also observed in patients who had received the low-dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs. CONCLUSION: Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses.

Post-transplant lymphoproliferative disorder in the pelvis successfully treated with consolidative radiotherapy.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLDs) are aggressive malignancies which represent one of the major post-transplant complications. However, treatment options vary significantly and localized disease may be curatively treated with radiotherapy (RT) or surgery. We report a case of recurrent rectal PTLD, which was successfully treated by chemoimmunotherapy followed by RT. CASE PRESENTATION: We describe a patient who developed a rectal lymphoproliferative lesion 11 years after kidney transplant, which was successfully treated with consolidative RT using 25.4 Gy sequential to chemoimmunotherapy (R-CHOP). RT was well tolerated and the patient showed no signs of grade 3 or 4 toxicity. This patient is free of recurrence 52 months after RT, with an overall survival of 62 months since diagnosis. CONCLUSION: Conventionally fractionated moderate-dose RT appears to be a tolerable and effective treatment option for localized PTLD if a sufficient systemic treatment cannot be applied.

Radiotherapy for aneurysmal bone cysts : A rare indication.

BACKGROUND: Aneurysmal bone cysts (ABC) are rapidly growing benign osseous lesions composed of blood-filled channels separated by fibrous septa. Since the value of external beam radiotherapy (EBRT) for ABC has not been well defined, the German Cooperative Group on Radiotherapy for Benign Diseases performed the national register study described herein. PATIENTS AND METHODS: Five German institutions collected data regarding clinical features, treatment concepts, and outcome for patients with ABC who had been referred for local EBRT over the past 30 years. RESULTS: Between 1990 and 2015, 10 patients with ABC were irradiated (5 female/5 male). Median age was 23 years (range 14-40 years). Involved sites were: spine (n = 3), sacrum/pelvis (n = 2), shoulder/scapula (n = 2), humerus (n = 1), femur (n = 1), and radius (n = 1). The median EBRT total and fractional doses were 28 Gy (range 5-40 Gy) and 2 Gy (range 1-2 Gy), respectively. Median follow-up was 65 months (range 12-358 months). Persistent pain relief was achieved for all patients. However, long-term follow-up response data were only available for 7/10 patients. All 7 patients exhibited a radiological response and experienced no recurrent disease activity or pain during follow-up. Acute and late radiogenic toxicities ≥ grade 3 and secondary malignancies were also not observed. CONCLUSION: Primary or adjuvant EBRT seems to be an effective and safe treatment option for persistent or recurrent ABC. Fractionated doses below 30 Gy may be recommended.