Interim PET-guided treatment for early-stage NLPHL: a subgroup analysis of the randomized GHSG HD16 and HD17 studies.

The optimal first-line treatment for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) diagnosed in early stages is largely undefined. We, therefore, analyzed 100 NLPHL patients treated in the randomized HD16 (early-stage favorable; n = 85) and HD17 (early-stage unfavorable; n = 15) studies. These studies investigated the omission of consolidation radiotherapy (RT) in patients with a negative interim positron emission tomography (iPET) (ie, Deauville score <3) after chemotherapy (HD16: 2× doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]; HD17: 2× escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone [BEACOPP] plus 2× ABVD). Patients with NLPHL treated in the HD16 and HD17 studies had 5-year progression-free survival (PFS) rates of 90.3% and 92.9%, respectively. Thus, the 5-year PFS did not differ significantly from that of patients with classical Hodgkin lymphoma treated within the same studies (HD16: P = .88; HD17: P = .50). Patients with early-stage favorable NLPHL who had a negative iPET after 2× ABVD and did not undergo consolidation RT tended to have a worse 5-year PFS than patients with a negative iPET who received consolidation RT (83% vs 100%; P = .05). There were 10 cases of NLPHL recurrence. However, no NLPHL patient died during follow-up. Hence, the 5-year overall survival rate was 100%. Taken together, contemporary Hodgkin lymphoma-directed treatment approaches result in excellent outcomes for patients with newly diagnosed early-stage NLPHL and, thus, represent valid treatment options. In early-stage favorable NLPHL, consolidation RT appears necessary after 2× ABVD to achieve the optimal disease control irrespective of the iPET result.

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.

Sarcopenia is associated with chemoradiotherapy discontinuation and reduced progression-free survival in glioblastoma patients.

PURPOSE: Sarcopenia may complicate treatment in cancer patients. Herein, we assessed whether sarcopenia measurements derived from radiation planning computed tomography (CT) were associated with complications and tumor progression during radiochemotherapy for glioblastoma. METHODS: Consecutive patients undergoing radiotherapy planning for glioblastoma between 2010 and 2021 were analyzed. Retrocervical muscle cross-sectional area (CSA) was measured via threshold-based semi-automated radiation planning CT analysis. Patients in the lowest sex-specific quartile of muscle measurements were defined as sarcopenic. We abstracted treatment characteristics and tumor progression from the medical records and performed uni- and multivariable time-to-event analyses. RESULTS: We included 363 patients in our cohort (41.6% female, median age 63 years, median time to progression 7.7 months). Sarcopenic patients were less likely to receive chemotherapy (p < 0.001) and more likely to be treated with hypofractionated radiotherapy (p = 0.005). Despite abbreviated treatment, they more often discontinued radiotherapy (p = 0.023) and were more frequently prescribed corticosteroids (p = 0.014). After treatment, they were more often transferred to inpatient palliative care treatment (p = 0.035). Finally, progression-free survival was substantially shorter in sarcopenic patients in univariable (median 5.1 vs. 8.4 months, p < 0.001) and multivariable modeling (hazard ratio 0.61 [confidence interval 0.46-0.81], p = 0.001). CONCLUSION: Sarcopenia is a strong risk factor for treatment discontinuation and reduced progression-free survival in glioblastoma patients. We propose that sarcopenic patients should receive intensified supportive care during radiotherapy and during follow-up as well as expedited access to palliative care.

Patterns of PET-positive residual tissue at interim restaging and risk of treatment failure in advanced-stage Hodgkin's lymphoma: an analysis of the randomized phase III HD18 trial by the German Hodgkin Study Group.

PURPOSE: Response-adapted treatment using early interim functional imaging with PET after two cycles of chemotherapy (PET-2) for advanced-stage Hodgkin's lymphoma (AS-HL) is the standard of care in several countries. However, the distribution of residual metabolic disease in PET-2 and the prognostic relevance of multiple involved regions have not been reported to date. METHODS: We retrospectively analyzed data from all PET-2-positive patients included in HD18. Residual tissue was visually compared with reference regions according to the Deauville score (DS). PET-2 positivity was defined as residual tissue with uptake above the liver (DS4). PFS was defined as the time from staging until progression, relapse, or death from any cause, or to the day when information was last received on the patient's disease status and analyzed using Kaplan-Meier and Cox regressions. Comparisons were made between patients with 1-2 and >2 positive regions in PET-2 as well as patients without PET-2-positive regions randomized into comparator arms of HD18. RESULTS: Between 2008 and 2014, 1964 patients with newly diagnosed AS-HL were recruited in HD18 and randomized following their PET-2 scan. Of these, 480 patients had a positive PET-2 and were eligible for this analysis. Upper and lower mediastinum in almost half of all patients: 230 (47.9%) and 195 (40.6%), respectively. 372 (77.5%) of patients have 1-2 positive regions in PET-2. 5y-PFS for patients with 1-2 regions was 91.7% (CI95: 88.7-94.6) vs. 81.8% (CI95: 74.2-90.1) for those with >2 regions with a corresponding hazard ratio (HR) of 2.2 (CI95: 1.2-4.0). Compared with patients without PET-2-positive disease receiving 6-8 cycles of chemotherapy, patients with 1-2 had a higher risk for a PFS event (HR 1.35; CI95 0.81-2.28), but it was not statistically significant (p=0.25). Patients with >2 PET-2-positive lesions had a significantly higher risk (HR 2.95; CI95: 1.62-5.37; p<0.001). CONCLUSION: PET-2-positive residuals of AS-HL are mostly located in the mediastinum, and a majority of patients have few affected regions. The risk of progression was twofold higher in patients with more than two positive regions in PET-2.

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.

Palliative care on the radiation oncology ward-improvements in clinical care through interdisciplinary ward rounds.

INTRODUCTION: Palliative care is essential for patients with terminal diseases and aims at effective symptom control. This may stand in opposition to radiation treatment as an oncological treatment modality. The hereby presented work demonstrates the successful integration of a palliative care service in the radiation oncology ward. METHODS: Since 2015, 1018 patients were seen by the palliative care service on the radiation oncology ward and have been analyzed in this single center study. To assess teaching efficacy of the consultation service, a survey was conducted among 15 radiation oncology residents. RESULTS: Cooperation between the two departments proved to be efficient with rising patient numbers. Palliative care was able to guide appropriate postdischarge care with the number of patients dying on the radiation oncology ward decreasing significantly (p = 0.009). The main topics for consultation were pain medication (92.3%), organization of postdischarge care (92.3%), and psycho-oncological support (84.6%). Most residents had a positive image of the palliative care service and consented on adjectives like "enriching", "empathic", "collegial", "professionally founded", and a "low threshold for consultation". All participants agreed that cooperation deepened their knowledge on palliative care. CONCLUSION: A synergistic cooperation between a palliative care consultation service and a radiation oncology department addresses patient symptoms on an individual level. It confers advanced knowledge on palliative care which is essential for resident education and patient treatment.

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.

The new German evidence-based guideline on diffuse large B-cell lymphoma-key aspects for radiation oncologists.

PURPOSE: Diffuse large B­cell lymphoma (DLBCL) is an aggressive lymphoma subtype treated successfully with immunochemotherapy. However, there are conflicting data on the role and impact of consolidative radiation therapy (RT). The publication of the national evidence-based guideline on DLBCL prompted us to review relevant passages on radiation oncology. METHODS: The following article reviews the evidence and recommendations given in the current German evidence-based guideline on DLBCL regarding RT and summarizes pivotal aspects. Additional literature is presented to provide a comprehensive background for the published recommendations. RESULTS: RT shall be administered to all patients with localized positron emission tomography(PET)-positive residues after completion of immunochemotherapy and should use a dose of 30-40 Gray in normofractionation. For RT planning, PET information before and after immunochemotherapy shall be used, with either a PET-CT in the RT treatment position or an image fusion to the planning CT. Conformal techniques shall be used for target volume coverage, with a risk-benefit evaluation for the individual patient. Additionally, RT may be used in the treatment context of various subtypes of DLBCL as well as in the recurrent or refractory treatment situation. CONCLUSION: RT remains an integral part of the treatment repertoire of DLBCL. With the use of PET-guided treatment, RT is indicated for patients with metabolically active tumors. In the context of the ongoing development of targeted therapies, new RT indications may evolve.

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.

Molecular predictors for decitabine efficacy in meningiomas - a pilot study.

PURPOSE: Effective chemotherapeutical agents for the treatment of meningiomas are still lacking. Previous in-vitro analyses revealed efficacy of decitabine (DCT), a DNA methyltransferase (DNMT) inhibitor established in the treatment of leukemia, in a yet undefined subgroup of meningiomas. METHODS: Effects of DCT on proliferation and viability was analyzed in primary meningioma cells by immunofluorescence and MTT assays, and cases were classified as drug responders and non-responders. Molecular preconditions for efficacy were analyzed using immunofluorescence for Ki67, DNMT1, and five oncogenes (TRIM58, FAM84B, ELOVL2, MAL2, LMO3) previously found to be differentially methylated after DCT exposition, as well as by genome-wide DNA methylation analyses. RESULTS: Efficacy of DCT (10µM) was found in eight (62%) of 13 meningioma cell lines 48 h after drug exposition (p < .05). DCT significantly reduced DNMT1 expression in all but two cell lines, and median ΔDNMT1 reduction 48 h after drug exposition was lower in DCT-resistant (-11.1%) than in DCT-sensitive (-50.5%, p = .030) cells. Rates of cell lines responsive to DCT exposition distinctly decreased to 25% after 72 h. No significant correlation of the patients´ age, sex, histological subtype, location of the paternal tumor, expression of Ki67, DNMT1 or the analyzed oncogenes with treatment response was found (p > .05, each). DCT efficacy was further independent of the methylation class and global DNA methylation of the paternal tumor. CONCLUSION: Early effects of DCT in meningiomas are strongly related with DNMT1 expression, while clinical, histological, and molecular predictors for efficacy are sparse. Kinetics of drug efficacy might indicate necessity of repeated exposition and encourage further analyses.

Confounders of intraoperative frozen section pathology during glioma surgery.

Although frozen section pathology (FSP) is commonly performed during surgery for glioma-suspicious lesions, confounders of accuracy are largely unknown. FSP and final diagnosis were compared in 398 surgeries for glioma-suspicious lesions. Diagnostic accuracy, risk factors for diagnostic shift from neoplastic to non-neoplastic tissue and vice versa according to the final diagnosis, and the impact on intraoperative and postoperative decision-making were analyzed. Diagnostic shift occurred in 70 cases (18%), and sensitivity, specificity, and the positive (PPV) and negative (NPV) predictive value of FSP were 82.5%, 77.8%, 99.4%, and 9.3%, respectively. No correlations between shift and patients' age and sex, sample fluorescence or volume, tumor location, correct information on the pathology form, final high- or low-grade histology, or molecular alterations were found (p > .05, each). Shift was more common after irradiation (25% vs 15%; p = .025) or chemotherapy (26% vs 15%; p = .022) than in treatment naïve cases and correlated with the type of surgery (p = .002). FSP altered intraoperative decision-making in 25 cases (6%). Postoperative shift led to repeated surgery in 12 patients (3%). In 45 cases, in which FSP and final diagnosis based on the same tissue, shift occurred in only 5 patients (11%), and sensitivity, specificity, PPV, and NPV for FSP were 77.4%, 78.6%, 88.9%, and 61.1%, respectively. No correlations between diagnostic shift and any of the analyzed variables were found (p > .05, each). Although accuracy of FSP during glioma surgery is sufficient, moderate NPV should be considered during intraoperative decision-making. While confounders are sparse, accuracy might be increased by repeated sampling. Diagnostic shift rarely alters postoperative treatment strategy.

Stage I-II nodular lymphocyte-predominant Hodgkin lymphoma: a multi-institutional study of adult patients by ILROG.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites >2 were associated with worse PFS (P < .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites >2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments.

The use of radiosensitizing agents in the therapy of glioblastoma multiforme-a comprehensive review.

BACKGROUND: Glioblastoma is the most common malignant brain tumor in human adults. Despite several improvements in resective as well as adjuvant therapy over the last decades, its overall prognosis remains poor. As a means of improving patient outcome, the possibility of enhancing radiation response by using radiosensitizing agents has been tested in an array of studies. METHODS: A comprehensive review of clinical trials involving radiation therapy in combination with radiosensitizing agents on patients diagnosed with glioblastoma was performed in the National Center for Biotechnology Information's PubMed database. RESULTS: A total of 96 papers addressing this matter were published between 1976 and 2021, of which 63 matched the subject of this paper. All papers were reviewed, and their findings discussed in the context of their underlining mechanisms of radiosensitization. CONCLUSION: In the history of glioblastoma treatment, several approaches of optimizing radiation-effectiveness using radiosensitizers have been made. Even though several different strategies and agents have been explored, clear evidence of improved patient outcome is still missing. Tissue-selectiveness and penetration of the blood-brain barrier seem to be major roadblocks; nevertheless, modern strategies try to circumvent these obstacles, using novel sensitizers based on preclinical data or alternative ways of delivery.

Digital transfer in radiation oncology education for medical students-single-center data and systemic review of the literature.

PURPOSE: Modern medical education demands innovative, competence-orientated concepts. The forced digital transfer of teaching due to the coronavirus pandemic also affected radiation oncology (RO). The following analysis investigates whether the attractivity of RO teaching at our faculty could be maintained during the pandemic and which possibilities exist to involve students (in active learning). The latter aspect is further elaborated on a broader scale by a systemic review of the literature on competence-orientated digital education. METHODS: Evaluation results and participation rates of clinical lectures in radiation oncology (RO) were analyzed between the winter semester 2018/2019 and the summer semester 2021. A systemic review of the literature on digital education in RO for medical students was conducted. RESULTS: Concerning evaluation results, a significant improvement for the 7th and 9th semesters was observed in comparison between the pre-pandemic and pandemic semesters (p = 0.046 and p = 0.05, respectively). Overall participation rates did not differ. However, the number of students attending > 75% of classes in the respective semester increased significantly between the pre-pandemic and pandemic period (median values: 38 vs. 79%, p = 0.046; 44 vs. 73%, p = 0.05; 45 vs. 64%, p = 0.05; 41 vs. 77%, p = 0.05; 41 vs. 71%, p = 0.05, for the 6th to 10th semester, respectively). CONCLUSION: The analysis demonstrates the possibility of efficient digital transfer of a core curriculum in RO to the digital era, with a more continuous participation of students. This transfer may enable amelioration of teaching quality and the introduction of innovative and interactive concepts in accordance with the literature.

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.

[Radiotherapy for the treatment of leukemia]. / Strahlentherapeutische Behandlung von Leukämien.

Background: Lymphoma cells are highly radiosensitive and consequently, radiation therapy is a rational addition to systemic therapy in the treatment of leukemia. Especially as a conditioning regimen before allogeneic stem cell transplantation, radiation therapy, in the form of total body irradiation, is an established concept. Objectives: The present work provides an overview on the execution and side effects of radiation treatment in leukemia. Especially (long-term) side effects after total body irradiation are presented. Materials and methods: A selective search in the database PubMed on radiation treatment of leukemia and on total body irradiation has been carried out, focusing on toxicities as well as technical and conceptional innovations. Results: Total body irradiation is a successful conditioning therapy before allogeneic stem cell transplantation and is accompanied by a diverse, but manageable, toxicity spectrum with endocrinological, cardiopulmonary, ophthalmological, nephrological and neurological long-term side effects as well as secondary neoplasia. In addition, low-dose radiotherapy may be utilized to treat myeloid sarcoma (chloroma). Conclusions: The variety of side effects after total body irradiation requires an interdisciplinary and long-term aftercare provided by radiation oncologists and medical oncologists/the transplantation team. Technical evolutions may result in a more selective targeting of the bone marrow and lymphatic organs. At the moment, these techniques are not established in clinical routine but are being evaluated in clinical trials.

PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy is standard of care for patients with early-stage unfavourable Hodgkin lymphoma. However, the use of radiotherapy can have long-term sequelae, which is of particular concern, as Hodgkin lymphoma is frequently diagnosed in young adults with a median age of approximately 30 years. In the German Hodgkin Study Group HD17 trial, we investigated whether radiotherapy can be omitted without loss of efficacy in patients who have a complete metabolic response after receiving two cycles of escalated doses of etoposide, cyclophosphamide, and doxorubicin, and regular doses of bleomycin, vincristine, procarbazine, and prednisone (eBEACOPP) plus two cycles of doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) chemotherapy (2 + 2). METHODS: In this multicentre, open-label, randomised, phase 3 trial, patients (aged 18-60 years) with newly diagnosed early-stage unfavourable Hodgkin lymphoma (all histologies) and an Eastern Cooperative Oncology Group performance status of 2 or less were enrolled at 224 hospitals and private practices in Germany, Switzerland, Austria, and the Netherlands. Patients were randomly assigned (1:1) to receive either standard combined-modality treatment, consisting of the 2 + 2 regimen (eBEACOPP consisted of 1250 mg/m2 intravenous cyclophosphamide on day 1, 35 mg/m2 intravenous doxorubicin on day 1, 200 mg/m2 intravenous etoposide on days 1-3, 100 mg/m2 oral procarbazine on days 1-7, 40 mg/m2 oral prednisone on days 1-14, 1·4 mg/m2 intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m2 intravenous bleomycin on day 8; ABVD consisted of 25 mg/m2 intravenous doxorubicin, 10 mg/m2 intravenous bleomycin, 6 mg/m2 intravenous vinblastine, and 375 mg/m2 intravenous dacarbazine, all given on days 1 and 15) followed by 30 Gy involved-field radiotherapy (standard combined-modality treatment group) or PET4-guided treatment, consisting of the 2 + 2 regimen followed by 30 Gy of involved-node radiotherapy only in patients with positive PET at the end of four cycles of chemotherapy (PET4; PET4-guided treatment group). Randomisation was done centrally and used the minimisation method and seven stratification factors (centre, age, sex, clinical symptoms, disease localisation, albumin concentration, and bulky disease), and patients and investigators were masked to treatment allocation until central review of the PET4 examination had been completed. With the final analysis presented here, the primary objective was to show non-inferiority of the PET4-guided strategy in a per-protocol analysis of the primary endpoint of progression-free survival. We defined non-inferiority as an absolute difference of 8% in the 5-year progression-free survival estimates between the two groups. Safety analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01356680. FINDINGS: Between Jan 13, 2012, and March 21, 2017, we enrolled and randomly assigned 1100 patients to the standard combined-modality treatment group (n=548) or to the PET4-guided treatment group (n=552); two patients in each group were found ineligible after randomisation. At a median follow-up of 46·2 months (IQR 32·7-61·2), 5-year progression-free survival was 97·3% (95% CI 94·5-98·7) in the standard combined-modality treatment group and 95·1% (92·0-97·0) in the PET4-guided treatment group (hazard ratio 0·523 [95% CI 0·226-1·211]). The between-group difference was 2·2% (95% CI -0·9 to 5·3) and excluded the non-inferiority margin of 8%. The most common grade 3 or 4 acute haematological adverse events were leucopenia (436 [83%] of 528 patients in the standard combined-modality treatment group vs 443 [84%] of 529 patients in the PET4-guided treatment group) and thrombocytopenia (139 [26%] vs 176 [33%]), and the most frequent acute non-haematological toxic effects were infection (32 [6%] vs 40 [8%]) and nausea or vomiting (38 [7%] vs 29 [6%]). The most common acute radiotherapy-associated adverse events were dysphagia (26 [6%] in the standard combined-modality treatment group vs three [2%] in the PET4-guided treatment group) and mucositis (nine [2%] vs none). 229 serious adverse events were reported by 161 (29%) of 546 patients in the combined-modality treatment group, and 235 serious adverse events were reported by 164 (30%) of 550 patients in the PET4-guided treatment group. One suspected unexpected serious adverse reaction (infection) leading to death was reported in the PET4-guided treatment group. INTERPRETATION: PET4-negativity after treatment with 2 + 2 chemotherapy in patients with newly diagnosed early-stage unfavourable Hodgkin lymphoma allows omission of consolidation radiotherapy without a clinically relevant loss of efficacy. PET4-guided therapy could thereby reduce the proportion of patients at risk of the late effects of radiotherapy. FUNDING: Deutsche Krebshilfe.

Definitive radiotherapy for localized follicular lymphoma staged by 18F-FDG PET-CT: a collaborative study by ILROG.

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 95.7%. For stage I, FFP was 74.1% vs 49.1% for stage II (P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.

Hybrid volumetric modulated arc therapy for hypofractionated radiotherapy of breast cancer: a treatment planning study.

PURPOSE: This study aims to evaluate the best possible practice using hybrid volumetric modulated arc therapy (H-VMAT) for hypofractionated radiation therapy of breast cancer. Different combinations of H­VMAT-a combination of three-dimensional radiotherapy (3D-CRT) and VMAT-were analyzed regarding planning target volume (PTV), dose coverage, and exposure to organs at risk (OAR). METHODS: Planning computed tomography scans were acquired in deep-inspiration breath-hold. A total of 520 treatment plans were calculated and evaluated for 40 patients, comprising six different H­VMAT plans and a 3D-CRT plan as reference. H­VMAT plans consisted of two treatment plans including 3D-CRT and VMAT. During H­VMAT planning, the use of hard wedge filters (HWF) and beam energies were varied. The reference plans were planned with mixed beam energies and the inclusion/omission of HWF. RESULTS: Compared to the reference treatment plans, all H­VMAT plans showed consistently better PTV dose coverage, conformity, and homogeneity. Additionally, OAR protection was significantly improved with several H­VMAT combinations (p < 0.05). The comparison of different H­VMAT combinations showed that inclusion of HWF in the base plan had a negative impact on PTV dose coverage, conformity, and OAR exposure. It also increased the planned monitor units and beam-on time. Advantages of using lower beam energies (6-MV photons) in both the base plan and in the VMAT supplementary dose were observed. CONCLUSION: The H­VMAT technique is an effective possibility for generating homogenous and conformal dose distributions. With the right choice of H­VMAT combination, superior OAR protection is achieved compared to 3D-CRT.

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.