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Hodgkin lymphoma (HL) is a B‐cell‐derived malignancy often affecting young adults. Allocation into risk groups is based on staging with positron emission tomography and computed tomography (PET/CT) and the presence or absence of risk factors. Standard treatment for early‐stage favorable classic HL (cHL) consists of two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), followed by 20 Gy involved‐site radiotherapy (IS‐RT). Two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) or a procarbazine‐free eBEACOPP variant plus two cycles of ABVD, followed by 30 Gy IS‐RT in the case of PET/CT positivity and no further treatment in the case of PET/CT negativity after chemotherapy should be considered in patients with early‐stage unfavorable cHL ≤ 60 years. If a less intensive approach is preferred and in individuals > 60 years, four cycles of A(B)VD followed by 30 Gy IS‐RT can be given. In advanced cHL, brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD) for four (in the case of PET/CT negativity after two cycles) or six cycles (in the case of PET/CT positivity after two cycles), followed by PET/CT‐guided 30 Gy IS‐RT should be considered in patients ≤ 60 years. Six cycles of nivolumab and AVD (N‐AVD) followed by PET/CT‐guided 30 Gy IS‐RT represents a less intensive alternative for younger patients and the preferred approach for patients > 60 years. Patients with cHL recurrence should receive checkpoint inhibitor‐containing salvage treatment followed by high‐dose chemotherapy and autologous stem cell transplantation if eligible. Treatment of nodular lymphocyte‐predominant HL differs from cHL in some situations and may contain an anti‐CD20 antibody. This guideline aims at providing recommendations for diagnosis, staging, treatment, and follow‐up of HL.

Intensified systemic chemotherapy has the highest primary cure rate for advanced-stage, classical Hodgkin lymphoma but this comes with a cost of severe and potentially life long, persisting toxicities. With the new regimen of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone (BrECADD), we aimed to improve the risk-to-benefit ratio of treatment of advanced-stage, classical Hodgkin lymphoma guided by PET after two cycles. This randomised, multicentre, parallel, open-label, phase 3 trial was done in 233 trial sites across nine countries. Eligible patients were adults (aged ≤60 years) with newly diagnosed, advanced-stage, classical Hodgkin lymphoma (ie, Ann Arbor stage III/IV, stage II with B symptoms, and either one or both risk factors of large mediastinal mass and extranodal lesions). Patients were randomly assigned (1:1) to four or six cycles (21-day intervals) of escalated doses of etoposide (200 mg/m2 intravenously on days 1–3), doxorubicin (35 mg/m2 intravenously on day 1), and cyclophosphamide (1250 mg/m2 intravenously on day 1), and standard doses of bleomycin (10 mg/m2 intravenously on day 8), vincristine (1·4 mg/m2 intravenously on day 8), procarbazine (100 mg/m2 orally on days 1–7), and prednisone (40 mg/m2 orally on days 1–14; eBEACOPP) or BrECADD, guided by PET after two cycles. Patients and investigators were not masked to treatment assignment. Hierarchical coprimary objectives were to show (1) improved tolerability defined by treatment-related morbidity and (2) non-inferior efficacy defined by progression-free survival with an absolute non-inferiority margin of 6 percentage points of BrECADD compared with eBEACOPP. An additional test of superiority of progression-free survival was to be done if non-inferiority had been established. Analyses were done by intention to treat; the treatment-related morbidity assessment required documentation of at least one chemotherapy cycle. This trial was registered at ClinicalTrials.gov (NCT02661503). Between July 22, 2016, and Aug 27, 2020, 1500 patients were enrolled, of whom 749 were randomly assigned to BrECADD and 751 to eBEACOPP. 1482 patients were included in the intention-to-treat analysis. The median age of patients was 31 years (IQR 24–42). 838 (56%) of 1482 patients were male and 644 (44%) were female. Most patients were White (1352 [91%] of 1482). Treatment-related morbidity was significantly lower with BrECADD (312 [42%] of 738 patients) than with eBEACOPP (430 [59%] of 732 patients; relative risk 0·72 [95% CI 0·65–0·80]; p<0·0001). At a median follow-up of 48 months, BrECADD improved progression-free survival with a hazard ratio of 0·66 (0·45–0·97; p=0·035); 4-year progression-free survival estimates were 94·3% (95% CI 92·6–96·1) for BrECADD and 90·9% (88·7–93·1) for eBEACOPP. 4-year overall survival rates were 98·6% (97·7–99·5) and 98·2% (97·2–99·3), respectively. BrECADD guided by PET after two cycles is better tolerated and more effective than eBEACOPP in first-line treatment of adult patients with advanced-stage, classical Hodgkin lymphoma. Takeda Oncology.

BackgroundGlioblastoma 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.MethodsA 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.ResultsA 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.ConclusionIn 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.

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 intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18–60 years were randomly assigned to receive either eight cycles of BEACOPPescalated (8×Besc group), six cycles of BEACOPPescalated (6×Besc group), or eight cycles of BEACOPP14 (8×B14 group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×Besc group, 711 in the 6×Besc group, and 710 in the 8×B14 group. Freedom from treatment failure was sequentially non-inferior for the 6×Besc and 8×B14 groups as compared with 8×Besc. 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0–87·7) for the 8×Besc group, 89·3% (86·5–92·1) for 6×Besc group, and 85·4% (82·1–88·7) for the 8×B14 group (97·5% CI for difference between 6×Besc and 8×Besc was 0·5–9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×Besc than with 8×Besc (97·5% CI 0·2–6·5). The 8×Besc group showed a higher mortality (7·5%) than the 6×Besc (4·6%) and 8×B14 (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1–96·1); and 225 (11%) of 2126 patients received additional radiotherapy. Treatment with six cycles of BEACOPPescalated followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPPescalated should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. Deutsche Krebshilfe and the Swiss Federal Government.

Background Despite improvements in surgical as well as adjuvant therapies over the last decades, the prognosis for patients with glioblastoma remains poor. Five-Aminolevulinic acid (5-ALA) induced porphyrins are already used for fluorescence-guided resection and as photosensitizer for photodynamic therapy. New findings reveal their potential use as sensitizing agents in combination with ionizing radiation. Methods We initiated a phase I/II dose escalation study, treating patients with recurrence of glioblastoma with oral 5-ALA concurrent to radiotherapy (RT). This prospective single-center study based in the University Hospital Münster aims to recruit 30 patients over 18 years of age with histologically verified recurrence of supratentorial glioblastoma in good performance status (KPS ≥ 60). Following a 3 + 3 dose-escalation design, patients having undergone re-resection will receive a 36 Gy RT including radiodynamic therapy fractions (RDT). RDT constitutes of oral administration of 5-ALA before the irradiation session. Two cohorts will additionally receive two fractions of neoadjuvant treatment three and two days before surgery. To determine the maximum tolerated dose of repeated 5-ALA-administration, the number of RDT-fractions will increase, starting with one to a maximum of eight fractions, while closely monitoring for safety and toxicity. Follow-up will be performed at two and five months after treatment. Primary endpoint will be the maximum tolerated dose (MTD) of repeated ALA-administration, secondary endpoints are event-free-, progression-free-, and overall-survival. Additionally, 5-ALA metabolites and radiobiological markers will be analysed throughout the course of therapy and tissue effects after neoadjuvant treatment will be determined in resected tissue. This protocol is in accordance with the SPIRIT guidelines for clinical trial protocols. Discussion This is the protocol of the ALA-RDT in GBM-study, the first-in-man evaluation of repeated administration of 5-ALA as a radiosensitizer for treatment of recurrent glioblastoma. Trial registration This study was approved by the local ethics committee of the Medical Association of Westphalia-Lippe and the University of Münster on 12.10.2022, the German federal institute for Drugs and medical devices on 13.10.2022 and the federal office for radiation protection on 29.08.2022. This trial was registered on the public European EudraCT database (EudraCT-No.: 2021-004631-92) and is registered under www.cliniclatrials.gov (Identifier: NCT05590689).

Syndecan-1 (CD138), a heparan sulfate proteoglycan, acts as a coreceptor for growth factors and chemokines and is a molecular marker associated with epithelial-mesenchymal transition during development and carcinogenesis. Resistance of Syndecan-1-deficient mice to experimentally-induced tumorigenesis has been linked to altered Wnt-responsive precursor cell pools, suggesting a potential role of Syndecan-1 in breast cancer cell stem function. However, the precise molecular mechanism is still elusive. Here, we decipher the functional impact of Syndecan-1 knockdown using RNA interference on the breast cancer stem cell phenotype of human triple-negative MDA-MB-231 and hormone receptor-positive MCF-7 cells in vitro employing an analytical flow cytometric approach. Successful Syndecan-1 siRNA knockdown was confirmed by flow cytometry. Side population measurement by Hoechst dye exclusion and Aldehyde dehydrogenase-1 activity revealed that Syndecan-1 knockdown in MDA-MB-231 cells significantly reduced putative cancer stem cell pools by 60% and 27%, respectively, compared to controls. In MCF-7 cells, Syndecan-1 depletion reduced the side population by 40% and Aldehyde dehydrogenase-1 by 50%, repectively. In MDA-MB-231 cells, the CD44(+)CD24(-/low) phenotype decreased significantly by 6% upon siRNA-mediated Syndecan-1 depletion. Intriguingly, IL-6, its receptor sIL-6R, and the chemokine CCL20, implicated in regulating stemness-associated pathways, were downregulated by >40% in Syndecan-1-silenced MDA-MB-231 cells, which showed a dysregulated response to IL-6-induced shifts in E-cadherin and vimentin expression. Furthermore, activation of STAT-3 and NFkB transcription factors and expression of a coreceptor for Wnt signaling, LRP-6, were reduced by >45% in Syndecan-1-depleted cells compared to controls. At the functional level, Syndecan-1 siRNA reduced the formation of spheres and cysts in MCF-7 cells grown in suspension culture. Our study demonstrates the viability of flow cytometric approaches in analyzing cancer stem cell function. As Syndecan-1 modulates the cancer stem cell phenotype via regulation of the Wnt and IL-6/STAT3 signaling pathways, it emerges as a promising novel target for therapeutic approaches.

The primary analysis of the GHSG HD16 trial indicated a significant loss of tumor control with PET-guided omission of radiotherapy (RT) in patients with early-stage favorable Hodgkin lymphoma (HL). This analysis reports long-term outcomes. Overall, 1150 patients aged 18–75 years with newly diagnosed early-stage favorable HL were randomized between standard combined-modality treatment (CMT) (2x ABVD followed by PET/CT [PET-2] and 20 Gy involved-field RT) and PET-2-guided treatment omitting RT in case of PET-2 negativity (Deauville score [DS] < 3). The study aimed at excluding inferiority of PET-2-guided treatment and assessing the prognostic impact of PET-2 in patients receiving CMT. At a median follow-up of 64 months, PET-2-negative patients had a 5-year progression-free survival (PFS) of 94.2% after CMT ( n  = 328) and 86.7% after ABVD alone ( n  = 300; HR = 2.05 [1.20–3.51]; p  = 0.0072). 5-year OS was 98.3% and 98.8%, respectively ( p  = 0.14); 4/12 documented deaths were caused by second primary malignancies and only one by HL. Among patients assigned to CMT, 5-year PFS was better in PET-2-negative ( n  = 353; 94.0%) than in PET-2-positive patients ( n  = 340; 90.3%; p  = 0.012). The difference was more pronounced when using DS4 as cut-off (DS 1-3: n  = 571; 94.0% vs. DS ≥ 4: n  = 122; 83.6%; p  < 0.0001). Taken together, CMT should be considered standard treatment for early-stage favorable HL irrespective of the PET-2-result.

PurposeDiffuse large B‑cell 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.MethodsThe 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.ResultsRT 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.ConclusionRT 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.

Background Cancer associated fibroblasts have become a target of interest in different malignancies for positron emission tomography (PET) imaging, using positron emitter labelled fibroblast activation protein inhibitors (FAPI). New data underline the advanced imaging properties of FAPI-PET/CT for the staging of esophageal cancer compared to standard imaging. Potential benefits of FAPI-PET/CT in radiation therapy planning are the subject of this investigation. Methods Ten patients with newly diagnosed esophageal cancer treated with radiochemotherapy (RCT) were retrospectively analyzed. All patients underwent [68Ga]OncoFAP-PET/CT in treatment position to facilitate radiation treatment planning. Six patients received neoadjuvant RCT as part of a trimodal therapy and four patients underwent definitive RCT. In five cases, restaging after initial treatment was performed with FAPI-PET/CT. Results [68Ga]OncoFAP-PET/CT based imaging showed a high correlation with the endoscopic staging for initial imaging. In three cases, new sites of disease were unmasked, not visible in CT- and endosonographic staging. [68Ga]OncoFAP-PET/CT based RT delineation offered good definition of clinical target volumes, especially in retro-/paracardial areas and the gastroesophageal junction. Conclusion [68Ga]OncoFAP-PET/CT may aid and improve radiation treatment planning for patients with esophageal cancer.