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To investigate the role of infra diaphragmatic intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT) for female Hodgkin Lymphoma (HL) patients and to estimate the risk of secondary cancer and ovarian failure.A comparative treatment planning study was performed on 14 patients, and the results were compared according to conventional dose-volume metrics. In addition, estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the bowel, the bladder and the rectum. For the ovaries, the risk of ovarian failure was estimated.The dosimetric findings demonstrate the equivalence between VMAT and IMPT in terms of target coverage. A statistically significant reduction of the mean and near-to-maximum doses was proven for the organs at risk. The EAR ratio estimated for IMPT to VMAT was 0.51 ± 0.32, 0.32 ± 0.35 and 0.05 ± 0.11 for the bowel, bladder and rectum, respectively. Concerning the risk of ovarian failure for the chronologic age ranging from 18 to 46 years, the expected net loss in fertility years ranged from 4.8 to 3.0 years for protons and 12.0 to 5.7 years for photons.This in-silico study confirmed the beneficial role of IMPT from a dosimetric point of view. Mathematical models suggested that the use of protons might be further advantageous due to the expected reduction of the risk of secondary cancer induction and its milder impact on the reduction of fertility.

Purpose Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. Methods The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives’ final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. Results The strategy retreat’s development process resulted in conception of the final vision “Innovative radiation oncology Together – Precise, Personalized, Human.” The first term “Innovative radiation oncology” comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term “together” underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. “Precise” mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. “Personalized” emphasizes biology-directed individualization of radiation treatment. Finally, “Human” underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. Conclusion The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.

BackgroundLife expectancy of patients with multiple myeloma (MM) has increased over the past decades, underlining the importance of local tumor control and avoidance of dose-dependent side effects of palliative radiotherapy (RT). Virtual noncalcium (VNCa) imaging from dual-energy computed tomography (DECT) has been suggested to estimate cellularity and metabolic activity of lytic bone lesions (LBLs) in MM.ObjectiveTo explore the feasibility of RT response monitoring with DECT-derived VNCa attenuation measurements in MM.MethodsThirty-three patients with 85 LBLs that had been irradiated and 85 paired non-irradiated LBLs from the same patients were included in this retrospective study. Irradiated and non-irradiated LBLs were measured by circular regions of interest (ROIs) on conventional and VNCa images in a total of 216 follow-up measurements (48 before and 168 after RT). Follow-ups were rated as therapy response, stable disease, or local progression according to the MD Anderson criteria. Receiver operating characteristic (ROC) analysis was performed to discriminate irradiated vs. non-irradiated and locally progressive vs. stable/responsive LBLs using absolute attenuation post-irradiation and percentage attenuation change for patients with pre-irradiation DECT, if available.ResultsAttenuation of LBLs decreased after RT depending on the time that had passed after irradiation [absolute thresholds for identification of irradiated LBLs 30.5–70.0 HU [best area under the curve [AUC] 0.75 (0.59–0.91)] and -77.0 to -22.5 HU [best AUC 0.85 (0.65–1.00)]/-50% and -117% to -167% proportional change of attenuation on conventional and VNCa images, respectively]. VNCa CT was significantly superior for identification of RT effects in LBLs with higher calcium content [best VNCa AUC 0.96 (0.91–1.00), best conventional CT AUC 0.64 (0.45–0.83)]. Thresholds for early identification of local irradiation failure were >20.5 HU on conventional CT [AUC 0.78 (0.68–0.88)] and >-27 HU on VNCa CT [AUC 0.83 (0.70–0.96)].ConclusionTherapy response of LBLs after RT can be monitored by VNCa imaging based on regular myeloma scans, which yields potential for optimizing the lesion-specific radiation dose for local tumor control. Decreasing attenuation indicates RT response, while above threshold attenuation of LBLs precedes local irradiation failure.

Purpose Cancer remains to be a leading cause of death worldwide, accounting for almost 10 million deaths in 2018. Radiation therapy (RT) is a common nonsurgical treatment in the management of patients with cancer that reduces disease recurrence and improves overall survival. However, preclinical RT modeling for accelerated bench-to-bedside translation of combination therapies is largely missing. While genetically engineered mouse models (GEMM) faithfully recapitulate human disease, conventional linear particle accelerator systems, commonly utilized in clinical settings, are not suited for state-of-the-art, image-guided targeted RT (IGRT) of these murine autochthonous tumors. Thus, we employed the CyberKnife (Accuray) platform for IGRT of GEMM-derived non-small cell lunger cancer (NSCLC) lesions. The CyberKnife (CK) is a stereotactic radiosurgery system (SRS) delivering high-dose RT precisely to the target area with minimal damage to the surrounding tissues based on intra-fraction image-guidance. Material and methods GEMM-derived NSCLC flank tumors driven by oncogenic Kras (KrasLSL-G12D/+) and deletion of Tp53 (Trp53fl/fl) were irradiated using the CK RT platform. We applied IGRT of 2, 4, 6, and 8 Gy using field sizes of 5 to 12.5 mm to average gross tumor volumes (GTV) of 0.9 cm3 (minimal 0.03 cm3) using Xsight Spine Tracking (Accuray) spine-based tumor localization. Results We found that a 0 mm planning target volume (PTV) margin is sufficient for IGRT of murine tumors using the CK. Furthermore, we analyzed the impact of CK-mediated IGRT on tumor infiltrating leukocytes by flow cytometry. We observed that higher RT doses (6-8 Gy) decreased absolute cell numbers of lymphocytes and myeloid cells by approximately half compared to low doses (2-4 Gy) or mock treated tumors within one hour, but even with low dose RT (2 Gy) tumor infiltrating leukocytes (TIL) were found to be reduced after 8 to 24 hours and recovered partly after 3 days. Conclusion In summary, we here demonstrate that the CK RT system allows for targeted IGRT of murine tumors with high precision and thus constitutes a novel promising platform for translational mouse RT studies, particularly performed in a longitudinal multimodal manner.

Purpose: The CeTeG/NOA-09 phase III trial demonstrated a significant survival benefit of lomustine–temozolomide chemoradiation in patients with newly diagnosed glioblastoma with methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. Following lomustine–temozolomide chemoradiation, late and prolonged pseudoprogression may occur. We here evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-l-tyrosine (FET) for differentiating pseudoprogression from tumor progression. Experimental Design: We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1–3). Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and dynamic FET uptake parameters (e.g., time-to-peak) were calculated. In patients with more than one FET-PET scan, relative changes of TBR values were evaluated, that is, an increase or decrease of >10% compared with the reference scan was considered as tumor progression or pseudoprogression. Diagnostic performances were evaluated using ROC curve analyses and Fisher exact test. Diagnoses were confirmed histologically or clinicoradiologically. Results: We identified 23 patients with 32 FET-PET scans. Within 5–25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBRmean calculated from the FET-PET performed 10 ± 7 days after the equivocal MRI showed the highest accuracy (87%) to identify pseudoprogression (threshold, Conclusions: The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine–temozolomide chemoradiation.

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.

Purpose: A primary analysis of the ongoing NIVAHL trial demonstrated unexpectedly high interim complete response rates to nivolumab-based first-line treatment in early-stage unfavorable Hodgkin lymphoma. However, biomarkers such as metabolic tumor volume (MTV) or total lesion glycolysis (TLG) and their change under treatment (ΔMTV and ΔTLG), measured on PET, might provide additional relevant information for response assessment in this setting. Hence, the current analysis aimed to investigate early response to checkpoint inhibitor therapy beyond conventional criteria. Patients and Methods: NIVAHL is a prospective, randomized phase II trial that recruited between April 2017 and October 2018. Patients in arms A and B were assessed for early treatment response after two courses of doxorubicin, vinblastine, and dacarbazine with two concomitant nivolumab infusions per cycle (2 × N-AVD) and 4 × nivolumab, respectively. In the current analysis, we included all 59 individuals with PET images available to the central review panel for quantitative analysis before April 30, 2019. Results: At interim restaging, we determined a mean ΔMTV and ΔTLG of −99.8% each in arm A after 2 × N-AVD, compared with −91.4% and −91.9%, respectively, for treatment group B undergoing 4 × nivolumab. This high decrease in MTV and TLG was observed regardless of the initial lymphoma burden. Conclusions: Our study showed that nivolumab-based first-line treatment leads to rapid, near-complete reduction of tumor metabolism in early-stage unfavorable Hodgkin lymphoma. Thus, PET-derived biomarkers might allow reduction or even omission of chemotherapy and radiotherapy. Furthermore, MTV and TLG could be also used to optimize immune checkpoint-targeting treatments in other cancers.

Background In radical radiochemotherapy (RCT) of inoperable non-small-cell lung cancer (NSCLC) typical prognostic factors include T- and N-stage, while there are still conflicting data on the prognostic relevance of gross tumor volume (GTV) and particularly its changes during RCT. The NCT03055715 study of the Young DEGRO working group of the German Society of Radiation Oncology (DEGRO) evaluated the prognostic impact of GTV and its changes during RCT. Methods A total of 21 university centers for radiation oncology from five different European countries (Germany, Switzerland, Spain, Belgium, and Austria) participated in the study which evaluated n = 347 patients with confirmed (biopsy) inoperable NSCLC in UICC stage III A/B who received radical curative-intent RCT between 2010 and 2013. Patient and disease data were collected anonymously via electronic case report forms and entered into the multi-institutional RadPlanBio platform for central data analysis. GTV before RCT (initial planning CT, GTV1) and at 40–50 Gy (re-planning CT for radiation boost, GTV2) was delineated. Absolute GTV before/during RCT and relative GTV changes were correlated with overall survival as the primary endpoint. Hazard ratios (HR) of survival analysis were estimated by means of adjusted Cox regression models. Results GTV1 was found to have a mean of 154.4 ml (95%CI: 1.5–877) and GTV2 of 106.2 ml (95% CI: 0.5–589.5), resulting in an estimated reduction of 48.2 ml (p p = 0.03) was found to be a stronger survival predictor than GTV1 (1.34 (0.9–2, p > 0.05). In patients with available data on both GTV1 and GTV2, absolute GTV1 before RT was not significantly associated with survival (HR 0–69, 0.32–1.49, p > 0.05) but GTV2 significantly predicted OS in a model adjusted for age, T stage, and chemotherapy, with an HR of 3.7 (1.01–13.53, p = 0.04) per 300 ml. The absolute decrease from GTV1 to GTV2 was correlated to survival, where every decrease by 50 ml reduced the HR by 0.8 (CI 0.64–0.99, p = 0.04). There was no evidence for a survival effect of the relative change between GTV1 and GTV2. Conclusion Our results indicate that independently of T stage, the re-planning GTV during RCT is a significant and superior survival predictor compared to baseline GTV before RT. Patients with a high absolute (rather than relative) change in GTV during RT show a superior survival outcome after RCT.

Background For meningiomas, complete resection is recommended as first-line treatment while stereotactic radiosurgery (SRS) is established for meningiomas of smaller size considered inoperable. If the patient´s medical condition or preference excludes surgery, SRS remains a treatment option. We evaluated the efficacy and safety of SRS in a cohort comprising these cases. Methods In this retrospective single-centre analysis we included patients receiving single fraction SRS either by modified LINAC or robotic guidance by Cyberknife for potentially resectable intracranial meningiomas. Treatment-related adverse events as well as local and regional control rates were determined from follow-up imaging and estimated by the Kaplan–Meier method. Results We analyzed 188 patients with 218 meningiomas. The median radiological, and clinical follow-up periods were 51.4 (6.2–289.6) and 55.8 (6.2–300.9) months. The median tumor volume was 4.2 ml (0.1–22), and the mean marginal radiation dose was 13.0 ± 3.1 Gy, with reference to the 80.0 ± 11.2% isodose level. Local recurrence was observed in one case (0.5%) after 239 months. The estimated 2-, 5-, 10- and 15-year regional recurrence rates were 1.5%, 3.0%, 6.6% and 6.6%, respectively. Early adverse events (≤ 6 months after SRS) occurred in 11.2% (CTCEA grade 1–2) and resolved during follow-up in 7.4% of patients, while late adverse events were documented in 14.4% (grade 1–2; one case grade 3). Adverse effects (early and late) were associated with the presence of symptoms or neurological deficits prior to SRS (p p Conclusion In this analysis SRS appears to be an effective treatment for patients with meningiomas eligible for complete resection and provides reliable long-term local tumor control with low rates of mild morbidity.

To investigate the performance of a narrow-scope knowledge-based RapidPlan (RP) model, for optimisation of intensity-modulated proton therapy (IMPT) plans applied to patients with locally advanced carcinoma in the gastroesophageal junction.A cohort of 60 patients was retrospectively selected; 45 were used to 'train' a dose-volume histogram predictive model; the remaining 15 provided independent validation. The performance of the RP model was benchmarked against manual optimisation. Quantitative assessment was based on several dose-volume metrics.Manual and RP-optimised IMPT plans resulted dosimetrically similar, and the planning dose-volume objectives were met for all structures. Concerning the validation set, the comparison of the manual vs RP-based plans, respectively, showed for the target (PTV): the homogeneity index was 6.3 ± 2.2 vs 5.9 ± 1.2, and V98% was 89.3 ± 2.9 vs 91.4 ± 2.2% (this was 97.2 ± 1.9 vs 98.8 ± 1.1 for the CTV). Regarding the organs at risk, no significant differences were reported for the combined lungs, the whole heart, the left anterior descending artery, the kidneys, the spleen and the spinal canal. The DA narrow-scope knowledge-based RP model was trained and validated for IMPT delivery in locally advanced cancer of the gastroesophageal junction. The results demonstrate that RP can create models for effective IMPT. Furthermore, the equivalence between manual interactive and unattended RP-based optimisation could be displayed. The data also showed a high correlation between predicted and achieved doses in support of the valuable predictive power of the RP method.

Background Consolidation brachytherapy is a critical treatment component for cervical cancer patients undergoing primary chemoradiation. Some patients are unsuitable for brachytherapy for a variety of reasons. The use of alternatives (LINAC-based stereotactic radiosurgery or external beam boosts) compromise oncologic results in cervical cancer patients. Thus, we evaluated the value of brachytherapy-like doses prescriptions using robotic radiosurgery (CyberKnife®, CR, Acuuray, Sunnyvale, CA, USA). Methods From 06/2011 to 06/2015, 31 patients (median age 53 years; range 30–77 years) with histologically proven FIGO stages IB-IVB cervical cancer underwent primary chemoradiation. All patients were either not suitable for intracervical brachytherapy for a variety of reasons or refused the brachytherapy. To achieve an adequate dose within the tumor, a CK boost was applied after fiducial implantation. In 29 patients, a dose of either five times 6 Gy or five times 5 Gy was prescribed to the target volume. Two patients received three times 5 Gy. The target dose was prescribed to the 70% isodose. Treatment toxicity was documented once weekly regarding vaginal mucositis, bladder, and bowel irritation according to CTCAE v. 4.03. If possible 3 months after completion of treatment intracervical curettage was performed to exclude residual tumor and the patients were followed up clinically. Sparing of organs at risk (OAR) and outcome in terms of local control (LC), overall survival (OS), and progression-free survival (PFS) were assessed. Results Of the 31 patients, 30 have completed CK boost therapy. The median follow-up time was 40 months (range 5–84 months). General treatment tolerability was good. Except for 1 patient, who had diarrhea grade 3, no treatment related side effects above grade 2 were reported. Sparing of OAR was excellent. The 1‑, 3‑, and 5‑year OS rates were 89, 60, and 57% respectively across all stages. Seven patients showed progression (28%), only two of them with local relapse (8%), resulting in an LC rate of 92% after 3 and 5 years. Mean PFS was 41 months (range 2–84 months). Patients with local recurrence had PFS of 5 and 8 months. Five patients developed distant metastases. Fifteen patients (48%) underwent intracervical curettage 3 months after completion of treatment of which 14 (93%) had complete pathologic response. Conclusion Brachytherapy remains the standard of care for patients diagnosed with cervical cancer and indication for primary chemoradiation. In terms of local control, CyberKnife®-based boost concepts provide excellent local control. It can be an alternative for patients who cannot receive adequate brachytherapy. Distant relapse still remains a challenge in this context.

Stereotactic radiosurgery (SRS) has evolved as widely accepted treatment option for small-sized (Koos I up to II) vestibular schwannoma (VS). For larger tumors (prevalent Koos VI), microsurgery or combined treatment strategies are mostly recommended. However, in patients not suited for microsurgery, SRS might also be an alternative to balance tumor control, hearing preservation and adverse effects. The purpose of this analysis was to evaluate the efficacy and toxicity of SRS for VS with regard to different Koos grades. All patients with untreated VS who received SRS at our center were included. Outcome analysis included tumor control, preservation of serviceable hearing based on median pure tone averages (PTA), and procedure-related adverse events rated by the Common Terminology Criteria for Adverse Events (CTCAE; v4.03) classification. In total, 258 patients (median age 58 years, range 21–84) were identified with a mean follow-up of 52 months (range 3–228 months). Mean tumor volume was 1.8 ml (range 0.1–18.5). The mean marginal dose was 12.3 Gy ± 0.6 (range 11–13.5). The cohort was divided into two groups: A (Koos grades I and II, n = 186) and B (Koos grades III and IV, n = 72). The actuarial tumor control rate was 98% after 2 years and 90% after 5 and 10 years. Koos grading did not show a significant impact on tumor control (p = 0.632) or hearing preservation (p = 0.231). After SRS, 18 patients (7%) had new transient or permanent symptoms classified by the CTCAE. The actuarial rate of CTCAE-free survival was not related to Koos grading (p = 0.093). Based on this selected population of Koos grade III and IV VS without or with only mild symptoms from brainstem compression, SRS can be recommended as the primary therapy with the advantage of low morbidity and satisfactory tumor control. The overall hearing preservation rate and toxicity of SRS was influenced by age and cannot be predicted by tumor volume or Koos grading alone.

The original version of this article unfortunately contained a mistake. The copyright holder for this article was incorrectly given as “© Springer-Verlag GmbH Germany, part of Springer Nature 2021,” but should have been “© The Author(s) 2021.” The original article has been corrected.

BACKGROUND In the present study, we characterized the long-term metabolic changes of brain metastases irradiated with stereotactic radiosurgery (SRS) by sequential dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value to diagnose delayed radiation-induced changes. MATERIAL AND METHODS From 2010–2021, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal or progressive MRI findings after SRS, and (iii) subsequently underwent at least two additional dynamic FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) and the dynamic FET PET parameter time-to-peak were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed histologically or clinicoradiologically. RESULTS We identified 36 patients with 98 FET PET scans (median number, 3; range, 2–6). Concurrent to SRS, 8 patients (22%) were treated with checkpoint inhibitors. Following SRS, suspicious MRI findings occurred after a median time of 11 months (range, 2–64 months). Subsequently, FET PET scans were acquired over a median period of 13 months (range, 5–60 months). The overall median follow-up time was 26 months (range, 8–101 months). Twenty-one patients (58%) had delayed radiation-induced changes. TBRs calculated from the last available FET PET scan showed the highest accuracy (92%) to identify delayed radiation-induced changes (threshold, 1.95; P CONCLUSION FET PET has a high diagnostic accuracy for characterizing the long-term changes of irradiated brain metastases.

Objective Microsurgical resection of cavernous sinus meningiomas (CSM) is associated with a high rate of incomplete resection, recurrence, and the risk for permanent, severe cranial nerve deficits. Stereotactic radiosurgery (SRS) has evolved as alternative treatment for primary and recurrent CSM. Here, we report about the long-term clinical and radiological follow-up (FU) of a unique cohort of patients with CSM treated with LINAC or Cyberknife based SRS. Methods In this single-center retrospective analysis, we include all patients with CSM who underwent single fraction SRS between 1993 and 2016. Clinical and radiological tumor control were evaluated by the Kaplan–Meier method. Additionally, patient data were analyzed in terms of symptom control and incidence of side effects rated by the common terminology criteria for adverse events (CTCAE; v4.03). Results 116 patients (female/male = 91/25; median age, 54 years; range, 33–82 years) were included. Mean tumor volume was 5.7 ± 3.3 cm3 (range, 0.6–16.2 cm3), the median marginal dose was 12.6 Gy applied to isodose levels of 75%. Median clinical FU was 55 months (range, 3–226 months). Tumor control was 98% after 2 and 5 years and 90% after 10 years. Twelve patients (10.3%) had permanent or transient radiation related toxicity (CTCAE I–III). An improvement of symptoms was observed in 26.7% of the symptomatic patients (n = 20 of 75). Conclusion SRS for CSM provides excellent long-term tumor and symptom control without considerable permanent side effects. Thus, SRS should be considered when counseling patients suffering from CSM.

Purpose The HD16 trial of the German Hodgkin Study Group (NCT00736320) demonstrated that radiation therapy in early-stage Hodgkin lymphoma without risk factors cannot be safely omitted, and therefore combined modality therapy (CMT) remains the standard treatment. To demonstrate the local effect of consolidating involved-field radiation therapy (IF-RT), we performed an analysis of the recurrence pattern of positron emission tomography (PET)-negative HD16 patients. Methods and Materials Between 2009 and 2015, 1150 patients with early-stage Hodgkin lymphoma without risk factors were randomly assigned to PET guided to 20 Gy IF-RT after 2 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy in the HD16 study of the German Hodgkin Study Group. The study was designed as a prospective randomized controlled trial. We correlated the localization of recurrence with the panel-based IF-RT plan, which was drawn up for all patients prospectively, blinded to treatment allocation. Accordingly, we were able to identify recurrences that occurred at least in part inside or outside of the (potential) radiation field (in-field and out-field, respectively). Results There were 328 and 300 PET-negative patients assigned to CMT and PET-guided treatment (ie, chemotherapy alone), respectively. Within a median 47-month follow-up, disease progression or recurrence was documented for 15 and 29 patients treated with and without IF-RT, respectively. Relapse localization was unknown in 1 CMT patient. Without IF-RT, 5-year incidence of in-field relapses was 10.5% (95% confidence interval, 6.5-14.6) compared with 2.4% (0.5-4.3) with CMT (P = .0008). There were no relevant differences in out-field recurrences (5-year incidence 4.1% [1.7-6.6] vs 6.6% [3.0-10.3], P = .54). There was no grade 4 toxicity observed during IF-RT, and incidence of second primary malignancies was similar in both groups. Conclusions PET-negative patients of the HD16 study showed no significant toxicity after 20 Gy IF-RT, and we demonstrated that omission of IF-RT resulted in more, particularly local, recurrences. Therefore, consolidation IF-RT should still be considered as standard therapy in this setting.

IntroductionConsolidation radiotherapy in intermediate stage Hodgkin´s lymphoma (HL) has been the standard of care for many years as involved field radiotherapy (IFRT) after chemotherapy. It included initially involved region(s). Based on randomized studies, radiation volumes could be reduced and involved site radiation therapy (ISRT) became the new standard. ISRT includes the initially affected lymph nodes. In young adults suffering from HL, infertility and hypogonadism are major concerns. With regard to these questions, we analyzed the influence of modern radiotherapy concepts such as consolidating ISRT in infradiaphragmatic involvement of HL after polychemotherapy.Patients and MethodsFive hundred twelve patients treated within German Hodgkin Study Group (GHSG) HD14 and HD17 trials were evaluated. We analyzed log-adjusted follicle-stimulating-hormone (FSH)- and luteinizing-hormone (LH)-levels of HD14-patients with infradiaphragmatic radiotherapy (IDRT) in comparison with HD14-patients, who had a supradiaphragmatic radiotherapy (SDRT). In a second step, we compared IFRT with ISRT of female HD17 patients regarding the effects on ovarian function and premature menopause.ResultsWe analyzed FSH- and LH-levels of 258 female and 241 male patients, all treated with IFRT. Of these 499 patients, 478 patients had SDRT and 21 patients had IDRT. In a multiple regression model, we could show that log-adjusted FSH (p=0.0006) and LH values (p=0.0127) were significantly higher after IDRT than after SDRT. The effect of IDRT on gonadal function was comparable to two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPesc). We compared the effect of IFRT with ISRT in thirteen female HD17 patients with infradiaphragmatic (ID) involvement. The mean ovarian dose after ISRT was significantly lower than after IFRT. The calculated proportion of surviving non-growing follicles (NGFs) increased significantly from 11.87% to 24.48% in ISRT compared to IFRT, resulting in a significantly longer calculated time to menopause. The younger the age at therapy, the greater the absolute time gain until menopause.ConclusionInfradiaphragmatic IFRT impairs gonadal function to a similar extent as two cycles of BEACOPPesc. In comparison, the use of ISRT target volume definition significantly reduced radiation dose to the ovaries and significantly extends the time interval from treatment to premature menopause.

Purpose: The CeTeG/NOA-09 phase III trial demonstrated a significant survival benefit of lomustine–temozolomide chemoradiation in patients with newly diagnosed glioblastoma with methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter. Following lomustine–temozolomide chemoradiation, late and prolonged pseudoprogression may occur. We here evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-l-tyrosine (FET) for differentiating pseudoprogression from tumor progression. Experimental Design: We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1–3). Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and dynamic FET uptake parameters (e.g., time-to-peak) were calculated. In patients with more than one FET-PET scan, relative changes of TBR values were evaluated, that is, an increase or decrease of >10% compared with the reference scan was considered as tumor progression or pseudoprogression. Diagnostic performances were evaluated using ROC curve analyses and Fisher exact test. Diagnoses were confirmed histologically or clinicoradiologically. Results: We identified 23 patients with 32 FET-PET scans. Within 5–25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBRmean calculated from the FET-PET performed 10 ± 7 days after the equivocal MRI showed the highest accuracy (87%) to identify pseudoprogression (threshold, Conclusions: The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine–temozolomide chemoradiation.

The original version of this article unfortunately contained mistakes. The name of the author Hess was corrected. Fig. 1 contained orthographic errors. Additionally, to ensure that the hyperlinks embedded in Fig. 1 can be accessed, Fig. 1 was added as Supplement 3. A reference to Supplement 3 has been added in the description of Fig. 1 in the article. The original article has been corrected. Korrektur zu 10.1007/s00066-021-01843-9

Purpose: We investigated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (18F-FET) PET for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastases (BM) since contrast-enhanced MRI often remains inconclusive. Methods: We retrospectively identified 40 patients with 107 BM secondary to melanoma (n = 29 with 75 BM) or non-small cell lung cancer (n = 11 with 32 BM) treated with ICI or TT who had 18F-FET PET (n = 60 scans) for treatment monitoring from 2015-2019. The majority of patients (n = 37; 92.5%) had radiotherapy during the course of disease. In 27 patients, 18F-FET PET was used for the differentiation of treatment-related changes from BM relapse following ICI or TT. In 13 patients, 18F-FET PET was performed for response assessement to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 months). In all lesions, static and dynamic 18F-FET PET parameters were obtained (i.e., mean tumor-to-brain ratios (TBR), time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathological findings as reference. Results: A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P = 0.003). Metabolic responders to ICI or TT on 18F-FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P = 0.004). Furthermore, at follow-up, time-to-peak values in metabolic responders increased significantly (P = 0.019). Conclusion:18F-FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.

Summary Background The German Hodgkin Study Group's HD18 trial established the safety and efficacy of PET-guided eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) for the treatment of advanced-stage Hodgkin lymphoma. However, because of a protocol amendment during the enrolment period (June 1, 2011) that changed standard treatment from eight to six cycles, the results of the HD18 trial have been partially immature. We report a prespecified 5-year follow-up analysis of the completed HD18 trial. Methods HD18 was an international, open-label, randomised, phase 3 trial done in 301 hospitals and private practices in five European countries. Patients aged 18–60 years with newly diagnosed, advanced-stage Hodgkin lymphoma and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited. After receiving an initial two cycles of eBEACOPP (1250 mg/m2 intravenous cyclophosphamide [day 1], 35 mg/m2 intravenous doxorubicin [day 1], 200 mg/m2 intravenous etoposide [day 1–3], 100 mg/m2 oral procarbazine [day 1–7], 40 mg/m2 oral prednisone [day 1–14], 1·4 mg/m2 intravenous vincristine [day 8], and 10 mg/m2 intravenous bleomycin [day 8]), patients underwent a contrast-enhanced CT and PET scan (PET-2). Patients with positive PET-2 were randomly assigned to receive standard therapy (an additional six cycles of eBEACOPP; ie, eight cycles in total) or experimental therapy (an additional six cycles of eBEACOPP plus 375 mg/m2 intravenous rituximab; ie, eight cycles in total) until June 1, 2011. After June 1, 2011, all patients with positive PET-2 were assigned to the updated standard therapy with an additional four cycles of eBEACOPP (ie, six cycles in total). Patients with negative PET-2 were randomly assigned (1:1) to receive standard therapy (an additional six cycles of eBEACOPP [ie, eight cycles in total] until June 1, 2011; an additional four cycles of eBEACOPP [ie, six cycles in total] after June 1, 2011) or experimental therapy (an additional two cycles of eBEACOPP; ie, four cycles in total). Randomisation was done centrally with the minimisation method, including a random component, stratified by centre, age, stage, international prognostic score, and sex. The primary endpoint was progression-free survival. HD18 aimed to improve 5-year progression-free survival by 15% in the PET-2-positive intention-to-treat cohort and to exclude inferiority of 6% or more in 5-year progression-free survival in the PET-2-negative per-protocol population. This study is registered with ClinicalTrials.gov , NCT00515554 , and is completed. Findings Between May 14, 2008, and July 18, 2014, 2101 patients were enrolled and 1945 were assigned to a treatment group according to their PET-2 result. In the PET-2-positive cohort, with a median follow-up of 73 months (IQR 59 to 94), 5-year progression-free survival was 89·9% (95% CI 85·7 to 94·1) in 217 patients assigned to eight cycles of eBEACOPP before the protocol amendment and 87·7% (83·1 to 92·4) in 217 patients assigned to eight cycles of rituximab plus eBEACOPP (p=0·40). Among 506 patients who received six cycles of eBEACOPP after the protocol amendment, 5-year progression-free survival was 90·1% (95% CI 87·2 to 92·9), with a median follow-up of 58 months (IQR 39 to 66). In the PET-2-negative cohort, with a median follow-up of 66 months (IQR 54 to 85) in the combined pre-amendment and post-amendment groups, 5-year progression-free survival was 91·2% (95% CI 88·4 to 93·9) in 446 patients who received eight or six cycles of eBEACOPP and 93·0% (90·6 to 95·4) in 474 patients who received four cycles of eBEACOPP (difference 1·9% [95% CI −1·8 to 5·5]). In the subgroup of PET-2-negative patients randomly assigned after protocol amendment, 5-year progression-free survival was 90·9% (95% CI 86·8 to 95·1) in 202 patients assigned to receive six cycles of eBEACOPP and 91·0% (86·6 to 95·5) in 200 patients assigned to receive four cycles of eBEACOPP (difference 0·1% [–5·9 to 6·2]). Interpretation Long-term follow-up confirms the efficacy and safety of PET-2-guided eBEACOPP in patients with advanced-stage Hodgkin lymphoma. The reduction from eight to four cycles of eBEACOPP represents a benchmark in the treatment of early-responding patients, who can now be potentially cured with a short and safe treatment approach. Funding Deutsche Krebshilfe, Swiss State Secretariat for Education, Research and Innovation SERI (Switzerland), and Roche Pharma. Translation For the German translation of the abstract see Supplementary Materials section.

PURPOSE We evaluated disease and treatment characteristics of patients with relapse after risk-adapted first-line treatment of early-stage, favorable, classic Hodgkin lymphoma (ES-HL). We compared second-line therapy with high-dose chemotherapy and autologous stem cell transplantation (ASCT) or conventional chemotherapy (CTx). METHODS We analyzed patients with relapse after ES-HL treated within the German Hodgkin Study Group HD10+HD13 trials. We compared, by Cox proportional hazards regression, progression-free survival (PFS) after relapse (second PFS) treated with either ASCT or CTx and performed sensitivity analyses with overall survival (OS) from relapse and Kaplan-Meier statistics. RESULTS A total of 174 patients’ disease relapsed after treatment in the HD10 (n = 53) and HD13 (n = 121) trials. Relapse mostly occurred > 12 months after first diagnosis, predominantly with stage I-II disease. Of 172 patients with known second-line therapy, 85 received CTx (49%); 70, ASCT (41%); 11, radiotherapy only (6%); and 4, palliative single agent therapies (2%). CTx was predominantly bleomycin, etoposide, doxorubicin cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP [68%]), followed by the combination regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (19%), or other regimens (13%). Patients aged > 60 years at relapse had shorter second PFS (hazard ratio [HR], 3.0; P = .0029) and were mostly treated with CTx (n = 33 of 49; 67%) and rarely with ASCT (n = 8; 16%). After adjustment for age and a disadvantage of ASCT after the more historic HD10 trial, we did not observe a significant difference in the efficacy of CTx versus ASCT for second PFS (HR, 0.7; 95% CI, 0.3 to 1.6; P = .39). In patients in the HD13 trial who were aged ≤ 60 years, the 2-year, second PFS rate was 94.0% with CTx (95% CI, 85.7% to 100%) versus 83.3% with ASCT (95% CI, 71.8% to 94.8%). Additional sensitivity analyses including OS confirmed these observations. CONCLUSION After contemporary treatment of ES-HL, relapse mostly occurred > 12 months after first diagnosis. Polychemotherapy regimens such as BEACOPP are frequently administered and may constitute a reasonable treatment option for selected patients with relapse after ES-HL.

Immune checkpoint inhibition (ICI) has been established as successful modality in cancer treatment. Combination concepts are used to optimize treatment outcome, but may also induce higher toxicity rates than monotherapy. Several rationales support the combination of radiotherapy (RT) with ICI as radioimmunotherapy (RIT), but it is still unknown in which clinical situation RIT would be most beneficial. Therefore, we have conducted a retrospective matched-pair analysis of 201 patients with advanced-stage cancers and formed two groups treated with programmed cell death protein 1 (PD-1) inhibitors only (PD1i) or in combination with local RT (RIT) at our center between 2013 and 2017. We collected baseline characteristics, programmed death ligand 1 (PD-L1) status, mutational status, PD-1 inhibitor and RT treatment details, and side effects according to the Common Terminology Criteria for Adverse Events (CTCAE) v.5.0. Patients received pembrolizumab (n = 93) or nivolumab (n = 108), 153 with additional RT. For overall survival (OS) and progression-free survival (PFS), there was no significant difference between both groups. After propensity score matching (PSM), we analyzed 96 patients, 67 with additional and 29 without RT. We matched for different covariates that could have a possible influence on the treatment outcome. The RIT group displayed a trend towards a longer OS until the PD1i group reached a survival plateau. PD-L1-positive patients, smokers, patients with a BMI &le, 25, and patients without malignant melanoma showed a longer OS when treated with RIT. Our data show that some subgroups may benefit more from RIT than others. Suitable biomarkers as well as the optimal timing and dosage must be established in order to achieve the best effect on cancer treatment outcome.

The authors have requested that this preprint be removed from Research Square.

Purpose The coronavirus pandemic is affecting global health systems, endangering daily patient care. Hemato-oncological patients are particularly vulnerable to infection, requiring decisive recommendations on treatment and triage. The aim of this survey amongst experts on radiation therapy (RT) for lymphoma and leukemia is to delineate typical clinical scenarios and to provide counsel for high-quality care. Methods A multi-item questionnaire containing multiple-choice and free-text questions was developed in a peer-reviewed process and sent to members of the radiation oncology panels of the German Hodgkin Study Group and the German Lymphoma Alliance. Answers were assessed online and analyzed centrally. Results Omission of RT was only considered in a minority of cases if alternative treatment options were available. Hypofractionated regimens and reduced dosages may be used for indolent lymphoma and fractures due to multiple myeloma. Overall, there was a tendency to shorten RT rather than to postpone or omit it. Even in case of critical resource shortage, panelists agreed to start emergency RT for typical indications (intracranial pressure, spinal compression, superior vena cava syndrome) within 24 h. Possible criteria to consider for patient triage are the availability of (systemic) options, the underlying disease dynamic, and the treatment rationale (curative/palliative). Conclusion RT for hemato-oncological patients receives high-priority and should be maintained even in later stages of the pandemic. Hypofractionation and shortened treatment schedules are feasible options for well-defined constellations, but have to be discussed in the clinical context.

PurposeThe described work aimed to avoid cancellations of indispensable treatments by implementing active patient flow management practices and optimizing infrastructure utilization in the radiation oncology department of a large university hospital and regional COVID-19 treatment center close to the first German SARS-CoV‑2 hotspot region Heinsberg in order to prevent nosocomial infections in patients and personnel during the pandemic.Patients and methodsThe study comprised year-to-date intervention analyses of in- and outpatient key procedures, machine occupancy, and no-show rates in calendar weeks 12 to 19 of 2019 and 2020 to evaluate effects of active patient flow management while monitoring nosocomial COVID-19 infections.ResultsActive patient flow management helped to maintain first-visit appointment compliance above 85.5%. A slight appointment reduction of 10.3% daily (p = 0.004) could still significantly increase downstream planning CT scheduling (p = 0.00001) and performance (p = 0.0001), resulting in an absolute 20.1% (p = 0.009) increment of CT performance while avoiding overbooking practices. Daily treatment start was significantly increased by an absolute value of 18.5% (p = 0.026). Hypofractionation and acceleration were significantly increased (p = 0.0043). Integrating strict testing guidelines, a distancing regimen for staff and patients, hygiene regulations, and precise appointment scheduling, no SARS-CoV‑2 infection in 164 tested radiation oncology service inpatients was observed.ConclusionIn times of reduced medical infrastructure capacities and resources, controlling infrastructural time per patient as well as optimizing facility utilization and personnel workload during treatment evaluation, planning, and irradiation can help to improve appointment compliance and quality management. Avoiding recurrent and preventable exposure to healthcare infrastructure has potential health benefits and might avert cross infections during the pandemic. Active patient flow management in high-risk COVID-19 regions can help Radiation Oncologists to continue and initiate treatments safely, instead of cancelling and deferring indicated therapies.

Background To investigate the role of intensity-modulated proton therapy (IMPT) compared to volumetric modulated arc therapy (VMAT), realised with RapidArc and RapidPlan methods (RA_RP) for neoadjuvant radiotherapy in locally advanced oesophagal cancer. Methods Twenty patients were retrospectively planned for IMPT (with two fields, (IMPT_2F) or with three fields (IMPT_3F)) and RA_RP and the results were compared according to dose-volume metrics. Estimates of the excess absolute risk (EAR) of secondary cancer induction were determined for the lungs. For the cardiac structures, the relative risk (RR) of coronary artery disease (CAD) and chronic heart failure (CHF) were estimated. Results Both the RA_RP and IMPT approached allowed to achieve the required coverage for the gross tumour volume, (GTV) and the clinical and the planning target volumes, CTV and PTV (V98% > 98 for CTV and GTV and V95% > 95 for the PTV)). The conformity index resulted in 0.88 ± 0.01, 0.89 ± 0.02 and 0.89 ± 0.02 for RA_RP, IMPT_2F and IMPT_3F respectively. With the same order, the homogeneity index for the PTV resulted in 5.6 ± 0.6%, 4.4 ± 0.9% and 4.5 ± 0.8%. Concerning the organs at risk, the IMPT plans showed a systematic and statistically significant incremental sparing when compared to RA_RP, especially for the heart. The mean dose to the combined lungs was 8.6 ± 2.9 Gy for RA_RP, 3.2 ± 1.5 Gy and 2.9 ± 1.2 Gy for IMPT_2F and IMPT_3F. The mean dose to the whole heart resulted to 9.9 ± 1.9 Gy for RA_RP compared to 3.7 ± 1.3 Gy or 4.0 ± 1.4 Gy for IMPT_2F or IMPT_3F; the mean dose to the left ventricle resulted to 6.5 ± 1.6 Gy, 1.9 ± 1.5 Gy, 1.9 ± 1.6 Gy respectively. Similar sparing effects were observed for the liver, the kidneys, the stomach, the spleen and the bowels. The EAR per 10,000 patients-years of secondary cancer induction resulted in 19.2 ± 5.7 for RA_RP and 6.1 ± 2.7 for IMPT_2F or 5.7 ± 2.4 for IMPT_3F. The RR for the left ventricle resulted in 1.5 ± 0.1 for RA_RP and 1.1 ± 0.1 for both IMPT sets. For the coronaries, the RR resulted in 1.6 ± 0.4 for RA_RP and 1.2 ± 0.3 for protons. Conclusion With regard to cancer of the oesophagogastric junction type I and II, the use of intensity-modulated proton therapy seems to have a clear advantage over VMAT. In particular, the reduction of the heart and abdominal structures dose could result in an optimised side effect profile. Furthermore, reduced risk of secondary neoplasia in the lung can be expected in long-term survivors and would be a great gain for cured patients.

Since the mid-1990s, 18F-fluorodeoxglucose (FDG)-positron emission tomography (PET) in combination with computed tomography has come to play a prominent role in the management of malignant lymphomas. One of the first PET applications in oncology was the detection of lymphoma manifestations at staging, where it has shown high sensitivity. Nowadays, this imaging modality is also used during treatment to evaluate the individual chemosensitivity and adapt further therapy accordingly. If the end-of-treatment PET is negative, irradiation in advanced-stage Hodgkin lymphoma patients can be safely omitted after highly effective chemotherapy. Thus far, lymphoma response assessment has mainly been performed using visual criteria, such as the Deauville five-point scale, which became the international standard in 2014. However, novel measures such as metabolic tumor volume or total lesion glycolysis have recently been recognized by several working groups and may further increase the diagnostic and prognostic value of FDG-PET in the future.

Immuno-oncological therapy concepts have already achieved great success in the treatment of a number of advanced malignancies, thereby rapidly gaining access to clinical practice. Immuncheckpoint inhibitors are also being reviewed in the adjuvant setting. In malignant melanoma, they have already shown efficacy. Different combination strategies of Immuncheckpoint inhibitors are currently undergoing clinical evaluation to further improve treatment outcomes. However, this has so far also been associated with a significantly increased immune-mediated rate of side effects. Effective and safe immuno-oncology requires good clinical management of immune-mediated side effects. Radiological assessment is challenging under immunotherapy and requires new standards (iRECIST). Encouraging is the fact that immunotherapy also causes long-term remissions in some of the patients. This raises the hope for a fundamentally curative potential of immuno-oncological therapeutic approaches.

Rationale: (18F)fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) for staging Hodgkin lymphoma may allow for accurate and reliable assessment of the metabolic tumour volume (MTV) as baseline risk factor. Our aim was to analyse the prognostic impact of MTV measurements, obtained by different means in advanced-stage Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD18 trial. Methods: Within the German Hodgkin Study Group trial HD18, 310 patients underwent 18F-FDG PET/CT scanning for staging which was available to the central review panel for quantitative analysis. We calculated the MTV by four different thresholding methods and performed receiver operating characteristic (ROC) analysis to evaluate the potential for prediction of early response determined by PET after two cycles (PET-2) dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). Logistic regression was used to evaluate its prognostic value concerning progression-free survival (PFS) and overall survival (OS). Results: All different MTV calculations used predicted PET-2 response to a moderate and comparable degree (area under the curve = 0.62-0.63, P = 0.01-0.06). With none of the measuring methods did the ROC curves point to any unique cut-off values, but indicated a wide range of possible cut-offs. However, none of the MTV measurements was prognostic for PFS (Hazard ratio 1.2-1.5, P = 0.15-0.52) or OS (Hazard ratio 1.0-1.5, P = 0.95 - 0.27). Conclusion: Baseline MTV as determined by different means, is a predictive factor for early response to eBEACOPP after two cycles. However, value as a prognostic factor after highly effective PET-2 adapted treatment strategy could not be observed.

In fruhen und intermediaren Stadien des Hodgkin-Lymphoms (HL) kann die uberwiegende Zahl der Patienten durch eine risikoadaptierte Chemo- und Strahlentherapie (RT) geheilt werden. Allerdings tragt die therapieassoziierte Langzeittoxizitat wesentlich zu Morbiditat und Mortalitat bei. Aktuelle Studien haben daher zum Ziel, die therapieassoziierte Toxizitat unter Erhalt bzw. weiterer Verbesserung der erreichten Tumorkontrolle zu reduzieren. Ziel war die Entwicklung einer Therapieleitlinie fur die fruhen und intermediaren Stadien des HL auf der Grundlage aktueller Studiendaten. Es erfolgte eine Analyse der Tumorkontrolle, des Gesamtuberlebens und der verfugbaren Toxizitatsdaten in aktuellen randomisierten Studien, Metaanalysen und relevanten retrospektiven Auswertungen. In den fruhen Stadien sind 2 Zyklen ABVD (Adriamycin, Bleomycin, Vinblastin, Dacarbazin) und 20 Gy Involved-Site-RT (IS-RT) aufgrund der hervorragenden Uberlebensdaten (HD10) und der Etablierung des kleineres Bestrahlungsfelds der IS-RT Therapiestandard. In den intermediaren Stadien kann mit 4 Zyklen ABVD und 30 Gy IF-RT (Involved-Field-RT) ein progressionsfreies Uberleben (PFS) von bis zu 83 % erzielt werden. Eine signifikante Verbesserung der Tumorkontrolle wurde bei hoherer Akuttoxizitat mit 2 Zyklen BEACOPPeskaliert (Bleomycin, Etoposid, Doxorubicin, Cyclophosphamid, Vincristin, Procarbazin, Prednison) und 2 Zyklen ABVD („2 + 2“; HD14) erreicht. Die in H10 angewandte 18FFDG-PET-basierte Applikation von 2 Zyklen BEACOPPeskaliert bei nach 2 Zyklen ABVD PET-positiven Patienten konnte bei einem signifikanten Teil der Patienten bei vergleichsweise gutem PFS die Therapieintensitat reduzieren. Es bedarf jedoch weiterer Daten zur Etablierung dieses Ansatzes. Daher werden aktuell „2 + 2“ + 30 Gy IS-RT bei Patienten bis 60 Jahre als Standard empfohlen. Die verfugbaren Daten unterstutzen die Rolle der RT in der erzielten Tumorkontrolle. Eine 18FFDG-PET-basierte RT kann als individueller Therapieansatz angewandt werden.

Die FDG-PET (Fluordesoxyglucose-Positronenemissionstomographie) ist eine Standarduntersuchung in der Bestimmung des Stadiums und des Therapieansprechens des Hodgkin-Lymphoms geworden. Im initialen Staging erlaubt die PET eine sichere Stadienzuordnung und bei unauffalligem osteomedullarem Befund den Verzicht auf die Knochenmarkbiopsie. Der pradiktive Wert der FDG-PET wahrend und nach der Chemotherapie bietet weiteren, deutlichen Zugewinn an Information. PET-gesteuerte Therapieregime wurden eingefuhrt, die die PET schon nach 2 Zyklen Chemotherapie zur weiteren Therapiestratifizierung einsetzen. Sowohl Protokolle, die eine Intensivierung der Therapie aufgrund einer positiven PET nutzen, als auch die Deeskalation der Therapie wegen einer unauffalligen, negativen PET haben Erfolge gezeigt. So kann z. B. bei negativer FDG-PET nach 2 Zyklen effektiver Chemotherapie fur fortgeschrittene Stadien die Therapie von ublicherweise 6 auf insgesamt nur 4 Zyklen verkurzt werden. Nach Chemotherapie kann in fortgeschrittenen Stadien bei negativer FDG-PET auserdem ohne Verlust an Therapiesicherheit auf eine erganzende Bestrahlung verzichtet werden. Fur fruhe und mittlere Stadien ist die Moglichkeit des Verzichts auf die Bestrahlung noch nicht gezeigt, jedoch werden belastbare Daten erwartet. Robuste und reproduzierbare Beurteilungskriterien fur die PET sind heute Standard bei der Interpretation der Untersuchung, sowohl in wissenschaftlichen Studien als auch in der taglichen klinischen Routine. Die sog. 5‑Punkte-Deauville-Skala ist derzeitiger Standard zur visuellen Analyse. Die Konsequenzen aus der jeweiligen Zuordnung berucksichtigen dabei sowohl die vorangegangene als auch die folgende Behandlung.

Die Behandlung der zumeist jungen Patienten mit einem Hodgkin-Lymphom (HL) fuhrt in den meisten Fallen zu einer dauerhaften Heilung. Durch kontinuierliche Behandlung der Patienten in klinischen Studien konnte wie bei keiner anderen Erkrankung eine Therapieoptimierung erfolgen. Anfangliche Grosfeldbestrahlung wurde nach und nach ebenso wie die Bestrahlungsdosis reduziert, und durch die Hinzunahme der Chemotherapie wurde die „combined modality“ etabliert. Es erfolgte eine selektive Literaturrecherche in der Datenbank Pubmed zum Thema Hodgkin-Lymphom und Radiotherapie. Aktuell pragen technische Fortschritte und neue Zielvolumenkonzepte die Planung und Durchfuhrung der Bestrahlung wie nie zuvor. Aufgrund der exzellenten Prognose der Patienten spielen akute, aber v. a. Langzeitnebenwirkungen eine wesentliche Rolle. Lungenfibrose, Herzinfarkt und sekundare Malignome sind mogliche Nebenwirkungen, deren Risiko durch sorgfaltige Bestrahlungsplanung und Bestrahlungsdurchfuhrung beeinflusst werden kann. Aus diesem Grund spielen Entwicklungen, wie die Bestrahlung in tiefer Inspiration (DIBH) und moderne Bestrahlungstechniken wie z. B. intensitatsmodulierte Radiotherapie (IMRT) und bildgefuhrte Radiotherapie (IGRT), eine ebenso herausragende Rolle im strahlentherapeutischen Alltag wie die neuen Zielvolumenkonzepte der International Lymphoma Radiation Oncology Group (ILROG). Durch die Verwendung moderner Techniken in der Bestrahlungsplanung und Bestrahlungsdurchfuhrung kann eine erhohte Prazision erreicht werden. Ebenso zeigen aktuelle Auswertungen, dass mit hoher Wahrscheinlichkeit auch ein positiver Einfluss auf die akuten und Langzeitnebenwirkungen genommen werden kann.

Background The primary analysis of the HD16 trial initiated in 2018 found that, in the treatment of early-stage favorable Hodgkin lymphoma (HL), involved-field radiotherapy (IF-RT) cannot be omitted from standard combined-modality treatment (CMT) without a clinically significant loss of tumor control. We thus complement the published analysis with prolonged follow-up and data on long-term toxicity. Methods Between 11/2009 and 12/2015, we enrolled 1150 patients aged 18-75 years with newly diagnosed HL in stages I or II without risk factors. Patients were randomized between standard CMT, with 2 cycles of ABVD followed by a centrally reviewed PET/CT-based restaging (PET-2) and 20 Gy IF-RT regardless of PET-2 result, and PET-2-guided treatment, with 2 cycles ABVD followed by 20 Gy IF-RT only in case of a positive PET-2 in terms of a Deauville score (DS) ≥3. Primary endpoint was PFS, analyzed according to Kaplan-Meier using Cox regression and log-rank test as applicable. We aimed at excluding inferiority of the PET-2-guided regimen in terms of a Hazard ratio (HR) of 3.01 or above in the PET-2-negative per-protocol cohort. Another aim was to assess the prognostic impact of PET-2 among those patients assigned to receive CMT. This follow-up analysis aims at repeating the main analyses with prolonged follow-up and complement efficacy results with long-term safety data. Findings With a median follow-up of 64 months, PET-2-negative patients had five-year PFS of 94.2% (95% CI 91.6-96.9) after CMT (n=328) and 86.7% (82.5-90.9) after ABVD alone in the PET-2-guided treatment group (n=300; HR 2.05 [1.20-3.51] including the non-inferiority margin; log-rank p=0.0072). The difference primarily resulted from recurrences that were at least in part located within the potential radiation field, with 5-year cumulative incidences of 2.0% (0.4-3.7) after CMT vs. 10.4% (6.7-14.1) after ABVD alone (p=0.0002). There was no difference regarding second primary malignancies, with 5-year cumulative incidences of 4.6% (2.1-7.1) after CMT vs. 4.2% (1.6-6.8) after ABVD (p=0.57). Five-year overall survival was 98.3% (96.9-99.8) and 98.8% (97.4-100), respectively (p=0.14), with 4 of the 12 documented deaths caused by second primary malignancies and only 1 by HL. Among patients assigned to receive CMT, PFS was superior in the PET-2-negative subgroup (DS 1-2) (n=353; 5-year PFS 94.0% [91.4-96.6]) compared with those having DS ≥3 (n=340; 90.3% [86.9-93.6]; p=0.012). The difference was more pronounced when the more commonly used cutoff of DS 4 was used for positivity (DS 1-3: n=571; 94.0% [91.9-96.0] vs. DS ≥4: n=122; 83.6% [76.6-90.6]; p After 5 years of follow-up, cardiac parameters showed normal outcomes in both randomized treatment groups and no relevant decrease compared with baseline values. Among 293 female patients aged 18-40 years at enrollment, the 5-year incidence of childbirth after therapy was 24.0% (15.9-32.2) after standard CMT vs. 17.9% (10.4-25.5) after PET-guided treatment. Conclusion We conclude that radiotherapy cannot be omitted from the treatment of early-stage favorable HL after a negative PET-2 without a clinically relevant and statistically significant loss of efficacy. We could not observe any disadvantage of standard CMT over PET-guided therapy in terms of acute or late toxicities. Overall survival is on a high level and not impaired by the omission of radiotherapy due to effective second-line therapies. Noteworthy the results of the HD16 trial became more pronounced with longer follow-up. This holds true for the per-protocol as well as for the intention-to-treat group. A positive PET after 2 cycles of ABVD in terms of DS ≥4 is associated with significantly inferior efficacy compared with a negative PET, indicating the need for further improvement in this group of patients. Taken together, we recommend that CMT is to be regarded as standard treatment for early-stage favorable HL. Disclosures Fuchs: BMS: Honoraria; Takeda: Consultancy, Honoraria; MSD: Honoraria; Celgene: Honoraria; Lukon: Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Topp: Amgen: Consultancy, Research Funding; Macrogeniecs: Research Funding; Regeneron: Consultancy, Research Funding; Gilead: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Universitatklinikum Wurzburg: Current Employment; Janssen: Consultancy; Celgene: Consultancy, Research Funding. Hertenstein: BMS: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Sanofi: Honoraria. Zijlstra: Takeda: Research Funding. Engert: Astra Zeneca: Consultancy, Honoraria; ADC Therapeutics: Consultancy; Tessa Therapeutics: Consultancy; Hexal: Honoraria; MSD: Honoraria; Amgen: Honoraria; BMS: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding.

Summary Background Advanced stage Hodgkin's lymphoma represents a heterogeneous group of patients with different risk profiles. Data suggests that interim PET assessment during chemotherapy is superior to baseline international prognostic scoring in terms of predicting long-term treatment outcome in patients with Hodgkin's lymphoma. We therefore hypothesised that early interim PET-imaging after two courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) might be suitable for guiding treatment in patients with advanced stage Hodgkin's lymphoma. We aimed to assess whether intensifying standard chemotherapy (BEACOPP escalated ) by adding rituximab would improve progression-free survival in patients with positive PET after two courses of chemotherapy. Methods In this open-label, international, randomised, phase 3 study, we recruited patients aged 18–60 years with newly diagnosed, advanced stage Hodgkin's lymphoma from 160 hospitals and 77 private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. Interim PET-imaging was done after two cycles of BEACOPP escalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPP escalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPP escalated (BEACOPP escalated group) or BEACOPP escalated plus rituximab (R-BEACOPP escalated group). PET-2 was assessed using a 5-point scale with 18 FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPP escalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m 2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPP escalated (day 0 and day 3 in cycle 4, day 1 in cycles 5–8). Randomisation was done centrally and used the minimisation method including a random component, stratified according to centre, age, stage, international prognostic score, and sex. The primary efficacy endpoint was 5 year progression-free survival, analysed in the intention-to-treat population. We are reporting this second planned interim analysis as the final report of the trial. The trial is registered with ClinicalTrials.gov, number NCT00515554. Findings Between May 14, 2008, and May 31, 2011, we enrolled 1100 patients. 440 patients had a positive PET-2 and were randomly assigned to either the BEACOPP escalated group (n=220) or the R-BEACOPP escalated group (n=220). With a median follow-up of 33 months (IQR 25–42) for progression-free survival, estimated 3 year progression-free survival was 91·4% (95% CI 87·0–95·7) for patients in the BEACOPP escalated group and 93·0% (89·4–96·6) for those in the R-BEACOPP escalated group (difference 1·6%, 95% CI −4·0 to 7·3; log rank p=0·99). Common grade 3–4 adverse events were leucopenia (207 [95%] of 218 patients in the BEACOPP escalated group vs 211 [96%] of 220 patients in the R-BEACOPP escalated group), and severe infections (51 [23%] vs 43 [20%] patients). Based on a futility analysis, the independent data monitoring committee recommended publication of this second planned interim analysis as the final result. Six (3%) of 219 patients in the BEACOPP escalated group and ten (5%) of 220 in the R-BEACOPP escalated group died; fatal treatment-related toxic effects occurred in one ( escalated group and three (1%) in the R-BEACOPP escalated group, all of them due to infection. Interpretation The addition of rituximab to BEACOPP escalated did not improve the progression-free survival of PET-2 positive patients with advanced stage Hodgkin's lymphoma. However, progression-free survival for PET-2 positive patients was much better than expected, exceeding even the outcome of PET-2-unselected patients in the previous HD15 trial. Thus, PET-2 cannot identify patients at high-risk for treatment failure in the context of the very effective German Hodgkin Study Group standard treatment for advanced stage Hodgkin's lymphoma. Funding Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

Background The primary analysis of the investigator-sponsored randomized multicenter phase II GHSG NIVAHL trial showed feasibility and excellent short-term efficacy of anti-PD1 based 1st-line treatment of early-stage unfavorable classical Hodgkin lymphoma (cHL). Achieving long-term disease control without excessive treatment-related morbidity is of utmost importance when developing innovative 1st-line cHL therapies. Duration of response and development of persisting immune-related toxicities are of concern in the setting of 1st-line anti-PD1 treatment. Methods NIVAHL enrolled treatment naïve early-stage unfavorable cHL patients at 28 German centers and individuals were randomized to either receive fully concomitant 4x Nivo-AVD (group A) or sequential 4xnivolumab, followed by 2x Nivo-AVD and 2x AVD (group B). Both groups received consolidative 30Gy IS-RT and the primary endpoint was complete response (CR) rate at end of study treatment. Detailed methods, patient characteristics and the primary endpoint analysis of NIVAHL have been recently published (Bröckelmann PJ et al. JAMA Oncol 2020). Herein we present extended follow-up of the NIVAHL trial to assess efficacy in terms of 2-year progression-free (PFS) and overall survival (OS) as well as safety with regards to long-term toxicities or organ impairment documented during the first year of follow-up after treatment. Results A total of 109 patients with cHL confirmed by central pathology review were enrolled between 04/2017 - 10/2018 and followed for a median of 20 and 21 months in groups A (n=55) and B (n=54), respectively, for the present analysis. All of the 7 patients deemed in partial remission (PR) at end of study treatment (EOT) converted into an ongoing CR after end of study without additional treatment during follow-up. With no relapse and no death observed since the primary analysis, the 2-year PFS estimates are 100% and 98% (95%CI 88-100%) in groups A and B, respectively, and the 2-year OS is 100% in both groups. With a median observation time for late-toxicities of 14 months after EOT (range 6-26 months) among 103 patients, any potentially treatment-related AE during follow-up was reported in 65% of patients (A: 74%, B: 56%). The highest documented CTCAE grade of late AEs was °I in 33%, °II in 25% and °III in 7% of patients with no °IV-V AEs observed. A total of 54% had at least one late event related to AVD, 47% to nivolumab and 32% to RT, with multiple relations attributable per event. Mean FEV1 and DLCOc did not decrease from baseline (91.1% -> 96.4% and 86.2% -> 83.3%, respectively). Decreased LVEF after EOT was reported in 2/56 patients with available data (4%). After EOT, 18% of patients required medication for adverse events. Corticosteroid ≥ and < 10mg prednisolone equivalent was required in 3% and 2% of patients, respectively, for a toxicity at any time during follow-up. No patient required corticosteroid treatment at last available follow-up. Most frequent toxicities reported after EOT included fatigue (21%), hypothyroidism (17%), respiratory tract disorders (16%), leukopenia (14%) and nervous system disorders (14%). Hypothyroidism was the event most frequently solely attributed to nivolumab during follow-up. The median time to onset after EOT was 5 months and affected patients nearly exclusively female (15/16 [94%]). After median follow-up of 10 months (range 0-21), hypothyroidism remained unchanged in 10 of 16 affected patients and resolved in 3 patients. Conclusion The excellent disease control of concomitant and sequential nivolumab and AVD in early-stage unfavorable cHL is confirmed with the currently available follow-up. Treatment-related toxicities ongoing or emerging during follow-up are predominantly associated with chemo- and/or RT. The most frequent nivolumab-associated late toxicity is hypothyroidism. No patient currently requires chronic corticosteroid treatment. Disclosures Bröckelmann: Bristol Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; MSD Sharp & Dohme: Research Funding. Keller:Bristol Myers Squibb: Honoraria, Other: Travel support, Speakers Bureau. Meissner:Celgene: Other: Travel support; Bristol Myers Squibb: Other: Travel support; Takeda: Other: Travel support; Merck Sharp & Dohme: Other: Travel support; Hexal: Other: Travel support. Trautmann:Bristol Myers Squibb: Honoraria. Kerkhoff:BMS: Honoraria. Hüttmann:Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Lead Discovery Center GmbH: Consultancy; Seattle Genetics: Research Funding; Gilead: Honoraria; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment; Roche: Other: Travel expenses; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Zimmermann:Takeda: Consultancy, Honoraria, Other: Travel Expenses; Bristol-Myers Squibb: Other: Travel Expenses; MSD: Other: Travel Expenses; Novartis: Other: Travel Expenses. Fuchs:Bristol Myers Squibb: Honoraria, Research Funding; Affimed: Honoraria; Takeda: Honoraria; Amgen: Honoraria; Celgene: Honoraria. von Tresckow:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding; MSD Sharp & Dohme: Honoraria, Research Funding; Roche: Honoraria; Kite/Gilead: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Borchmann:Takeda: Research Funding; Bristol Myers Squibb: Research Funding. Engert:Bristol Myers Squibb: Honoraria, Research Funding; Affimed Therapeutics: Research Funding; Takeda: Honoraria, Research Funding; MSD Sharp & Dohme: Honoraria; AstraZeneca: Honoraria; Sandoz: Honoraria. OffLabel Disclosure: Nivolumab 240mg Q2W alone or in combination with AVD for 1st-line treatment of classical Hodgkin lymphoma.

BACKGROUND The CeTeG/NOA-09 trial demonstrated a significant survival benefit of radiotherapy plus lomustine-temozolomide chemotherapy in glioblastoma patients with methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter compared to standard temozolomide chemoradiation (1). However, data on pseudoprogression following treatment according to the CeTeG/NOA-09 trial is lacking. Due to the limited specificity of conventional MRI we evaluated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of pseudoprogression from actual tumor progression. METHODS Twenty-one patients with newly diagnosed IDH-wildtype glioblastoma and methylated MGMT promoter with conventional MRI findings suspicious for tumor progression according to RANO criteria (2) after radiotherapy completion were investigated using FET PET. The maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) were calculated. Pseudoprogression was diagnosed neuropathologically or clinicoradiologically (i.e, if (i) a stable clinical course, (ii) stable or improved MRI findings, and (iii) no treatment change occurred within the next six months). Diagnostic performance of FET PET parameters was evaluated using receiver-operating-characteristic (ROC) analyses and Fisher’s exact test. Imaging results were also related to progression-free survival (PFS). RESULTS Pseudoprogression was identified in 9 of 21 patients (43%). In the majority of patients (n=8; 89%), pseudoprogression was diagnosed clinicoradiologically. The median time between radiotherapy completion and pseudoprogression was nine weeks (range, 5-25 weeks). ROC analysis yielded an optimal cutoff value of 1.95 for TBRmean to differentiate between pseudoprogression and tumor progression (sensitivity, 89%; specificity, 75%; accuracy, 81%; area under the curve, 0.72±0.13; P = 0.008). CONCLUSIONS In a considerable number of patients, pseudoprogression may occur following radiotherapy plus off-study lomustine-temozolomide chemotherapy according to the CeTeG/NOA-09 trial. FET PET appears of value for the differentiation of pseudoprogression from tumor progression in this group of patients. Literature: 1. Herrlinger et al., 2019 Lancet; 2. Wen et al., 2010 J Clin Oncol

PURPOSE Recently, the RANO group has analyzed the additional diagnostic value of amino acid PET in patients with primary and secondary brain tumors and recommended the use of this imaging technique in addition to conventional MRI. Here, we investigated the value of PET using the radiolabled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastases (BM) since contrast-enhanced MRI often remains inconclusive. METHODS We retrospectively identified 40 patients with 107 BM secondary to melanoma (n=29 with 75 BM) or non-small cell lung cancer (n=11 with 32 BM) treated with ICI or TT who had FET PET (n=60 scans) for treatment monitoring from 2015–2019. The majority of patients (n=37; 92.5%) had radiotherapy during the course of disease. In 27 patients, FET PET was used for the differentiation of treatment-related changes from BM relapse following ICI or TT. In 13 patients, FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 months). In all lesions, static and dynamic FET PET parameters were obtained (i.e., mean tumour-to-brain ratios (TBR), time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathological findings as reference. RESULTS A TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P=0.003). Metabolic Responders to ICI or TT on FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P=0.004). Furthermore, at follow-up, time-to-peak values in metabolic responders increased significantly (P=0.019). CONCLUSIONS FET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.

PURPOSE The optimal treatment of newly diagnosed nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is ill defined. We therefore conducted a retrospective analysis using the database of the German Hodgkin Study Group (GHSG). PATIENTS AND METHODS The long-term course of 471 patients with NLPHL (early stages, n = 251; intermediate stages, n = 76; advanced stages, n = 144) who had received stage-adapted first-line treatment in the randomized GHSG HD7 to HD15 studies was investigated. Treatment consisted of radiotherapy alone, chemotherapy alone, or combined-modality approaches. RESULTS The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Patients were mostly male (75.8%). The median observation time was 9.2 years. At 10 years, progression-free survival and overall survival estimates were 75.5% and 92.1% (early stages, 79.7% and 93.3%; intermediate stages, 72.1% and 96.2%; advanced stages, 69.8% and 87.4%), respectively. A total of 48 patients (10.2%) developed a second malignancy during follow-up (non-Hodgkin lymphoma, n = 13; leukemia, n = 6; solid tumor, n = 25; unspecified malignancy, n = 4). Death occurred in 43 patients (9.1%). However, only a minority of deaths were NLPHL related (n = 10), whereas second malignancies (n = 20) and nonmalignant conditions possibly associated with radiotherapy or chemotherapy (n = 13) caused the death in the majority of patients. CONCLUSION The overall outcome of patients with NLPHL who had received Hodgkin lymphoma–directed first-line treatment in randomized GHSG trial protocols was good. Nonetheless, treatment optimization is still necessary to reduce toxicity in standard-risk patients and to improve the prognosis in high-risk patients.

The large mediastinal mass (LMM) at initial staging represents a risk factor in Hodgkin lymphoma (HL) and is measured by X-ray. Depending on location of the LMM, different results can occur regardless of the initial lymphoma volume. To assess this risk factor more accurately, we evaluated the method of volumetry in 77 patients of HD13/14 study of the German Hodgkin Study Group. Furthermore, volume calculations based on three or only one diameter, were performed to simplify volume assessment. Inter-rater reliability was good for all methods. The 3-diameter measurement produced larger volumes than volumetric assessment with an intraclass correlation coefficient (ICC) of 0.93, which could be improved to 0.95 by multiplying volumes with a correction factor of 0.86. The 1-dimensional measurement strongly overestimated the volume with an ICC of 0.7. In conclusion, the simplified volume estimation based on 3 largest diameters provides a reliable concept for the staging of HL patients.

Immune checkpoint inhibition (ICI) targeting the programmed death receptor 1 (PD-1) has shown promising results in the fight against cancer. Systemic anti-tumor reactions due to radiation therapy (RT) can lead to regression of non-irradiated lesions (NiLs), termed "abscopal effect" (AbE). Combination of both treatments can enhance this effect. The aim of this study was to evaluate AbEs during anti-PD-1 therapy and irradiation. We screened 168 patients receiving pembrolizumab or nivolumab at our center. Inclusion criteria were start of RT within 1 month after the first or last application of pembrolizumab (2 mg/kg every 3 weeks) or nivolumab (3 mg/kg every 2 weeks) and at least one metastasis outside the irradiation field. We estimated the total dose during ICI for each patient using the linear quadratic (LQ) model expressed as 2 Gy equivalent dose (EQD2) using α/β of 10 Gy. Radiological images were required showing progression or no change in NiLs before and regression after completion of RT(s). Images must have been acquired at least 4 weeks after the onset of ICI or RT. The surface areas of the longest diameters of the short- and long-axes of NiLs were measured. One hundred twenty-six out of 168 (75%) patients received ICI and RT. Fifty-three percent (67/126) were treated simultaneously, and 24 of these (36%) were eligible for lesion analysis. AbE was observed in 29% (7/24). One to six lesions (mean = 3 ± 2) in each AbE patient were analyzed. Patients were diagnosed with malignant melanoma (MM) (n = 3), non-small cell lung cancer (NSCLC) (n = 3), and renal cell carcinoma (RCC) (n = 1). They were irradiated once (n = 1), twice (n = 2), or three times (n = 4) with an average total EQD2 of 120.0 ± 37.7 Gy. Eighty-two percent of RTs of AbE patients were applied with high single doses. MM patients received pembrolizumab, NSCLC, and RCC patients received nivolumab for an average duration of 45 ± 35 weeks. We demonstrate that 29% of the analyzed patients showed AbE. Strict inclusion criteria were applied to distinguish the effects of AbE from the systemic effect of ICI. Our data suggest the clinical existence of systemic effects of irradiation under ICI and could contribute to the development of a broader range of cancer treatments.

PURPOSE Combined-modality treatment (CMT) with 2× ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) and small-field radiotherapy is standard of care for patients with early-stage favorable Hodgkin lymphoma (HL). However, the role of radiotherapy has been challenged. Positron emission tomography (PET) after 2× ABVD (PET-2) might help to predict individual outcomes and guide treatment. METHODS Between November 2009 and December 2015, we recruited patients age 18 to 75 years with newly diagnosed, early-stage favorable HL for this international randomized phase III trial. Patients were assigned to standard CMT of 2× ABVD and 20-Gy involved-field radiotherapy or PET-guided treatment, omitting involved-field radiotherapy after negative PET-2 (Deauville score < 3). Primary objectives were to exclude inferiority of 10% or more in 5-year progression-free survival (PFS) of ABVD alone compared with CMT in a per-protocol analysis among PET-2–negative patients (noninferiority margin for hazard ratio, 3.01) and to confirm PET-2 positivity (Deauville score ≥ 3) as a risk factor for PFS among CMT-treated patients. RESULTS We enrolled 1,150 patients. Median follow-up was 45 months. Among 628 PET-2–negative, per-protocol–treated patients, 5-year PFS was 93.4% (95% CI, 90.4% to 96.5%) with CMT and 86.1% (95% CI, 81.4% to 90.9%) with ABVD (difference 7.3% [95% CI, 1.6% to 13.0%]; hazard ratio, 1.78 [95% CI, 1.02 to 3.12]). Five-year overall survival was 98.1% (95% CI, 96.5% to 99.8%) with CMT and 98.4% (95% CI, 96.5% to 100.0%) with ABVD. Among 693 patients who were assigned to CMT, 5-year PFS was 93.2% (95% CI, 90.2% to 96.2%) among PET-2–negative patients and 88.4% (95% CI, 84.2% to 92.6%) in PET-2–positive patients ( P = .047). When using the more common liver cutoff (Deauville score, 4) for PET-2 positivity, the difference was more pronounced (5-year PFS, 93.1% [95% CI, 90.7% to 95.5%] v 80.9% [95% CI, 72.2% to 89.7%]; P = .0011). CONCLUSION In early-stage favorable HL, a positive PET after two cycles ABVD indicates a high risk for treatment failure, particularly when a Deauville score of 4 is used as a cutoff for positivity. In PET-2–negative patients, radiotherapy cannot be omitted from CMT without clinically relevant loss of tumor control.

As part of the foundation of the German Hodgkin Study Group (GHSG) in 1978, a central radiotherapy (RT) reference centre was established to evaluate and to improve the quality of treatment. During the study generations, the quality assurance programs (QAP) were continued and adapted to the demands of each study. The purpose of this article is to demonstrate the results of the fifth study generation and to compare them to the previous findings. With the start of the fourth GHSG study generation (HD10–12), a central prospective review of all diagnostic images was established to create an individual treatment plan for each early stage study patient. The quality of involved field RT was retrospectively evaluated by an expert panel of radiation oncologists. In the fifth study generation (HD13–15), the retrospective review of radiotherapy performed was refined and the results were compared with the findings of the fourth generation. The expert panel analyzed the RT planning and application of 1037 (28 %) patients (HD13 n = 465, HD14 n = 572). Simulation films were available in 85 % of cases and verification films in 87 %. RT was assessed as major violation in 46 % (HD13 = 38 %, HD14 = 52 %), minor violation in 9 % (HD13 = 9 %, HD14 = 9 %) and according to the protocol in 45 % (HD13 = 52 %, HD14 = 38 %). The value for QAP of RT within the GHSG trials is well known. Still there were several protocol violations. In the future, the QAP program has to be adapted to the requirements of “modern RT” in malignant lymphoma.

Immune checkpoint inhibition with ipilimumab has revolutionized cancer immunotherapy and significantly improved outcomes of patients with advanced malignant melanoma. Local peripheral treatments (LPT), such as radiotherapy or electrochemotherapy, have been shown to modulate systemic immune responses, and preliminary data have raised the hypothesis that the combination of LPT with systemic immune checkpoint blockade might be beneficial. Clinical data from 127 consecutively treated melanoma patients at four cancer centers in Germany and Switzerland were analyzed. Patients received either ipilimumab (n = 82) or ipilimumab and additional LPT (n = 45) if indicated for local tumor control. The addition of LPT to ipilimumab significantly prolonged overall survival (OS; median OS 93 vs. 42 weeks, unadjusted HR, 0.46; P = 0.0028). Adverse immune-related events were not increased by the combination treatment, and LPT-induced local toxicities were in most cases mild. In a multivariable Cox regression analysis, we show that the effect of added LPT on OS remained statistically significant after adjusting for BRAF status, tumor stage, tumor burden, and central nervous system metastases (adjusted HR, 0.56; 95% confidence interval, 0.31–1.01, P = 0.05). Our data suggest that the addition of LPT to ipilimumab is safe and effective in patients with metastatic melanoma irrespective of clinical disease characteristics and known risk factors. Induction of antitumor immune responses is most likely the underlying mechanism and warrants prospective validation. Cancer Immunol Res; 4(9); 744–54. ©2016 AACR.

A Correction to this paper has been published: 10.1007/s00066-020-01698-6

Importance In early-stage unfavorable classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients who survive cHL. Objective To evaluate efficacy of 2 experimental nivolumab-based first-line treatment strategies in patients with early-stage unfavorable cHL. Design, Setting, and Participants This was an open-label, multicenter, phase 2 randomized clinical trial, open between April 2017 and October 2018. The trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. Eligibility was defined by age 18 to 60 years, cHL confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factor[s]), and absence of serious concomitant disease or organ dysfunction. Among 110 enrolled patients, 109 were eligible. Interventions Systemic therapy, per random assignment (1:1) to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy. Main Outcomes and Measures Complete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group. Results Of 109 patients included in this study, 65 (59.6%) were women, and the median (range) age was 27 (18-60) years. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 54 of 54 (100%) and 49 of 51 (96%) response-eligible patients, respectively, achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. Among 101 patients eligible for primary end point analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month progression-free survival was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy. Conclusions and Relevance Both strategies combining nivolumab and AVD are feasible and resulted in high remission rates. Despite narrowly missing the efficacy benchmark in the concomitant group, the excellent 12-month progression-free survival and the unexpectedly high CR rate after 4 doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage cHL. Trial Registration ClinicalTrials.gov Identifier:NCT03004833