Das Hodgkin-Lymphom ist eine maligne Erkrankung des lymphatischen Systems, die anhand der modifizierten Ann-Arbor-Klassifikation in 4 Stadien eingeteilt wird und zusätzlich nach dem Vorliegen von B‑Symptomen differenziert werden kann. Zur weiteren Risikostratifizierung dient die Einteilung der German Hodgkin Study Group (GHSG) in frühe, intermediäre und fortgeschrittene Stadien. Für frühe Stadien stellt bei Patient*innen ≤ 60 Jahre eine kombinierte Chemoradiotherapie aus 2 Zyklen ABVD mit anschließender Involved-Site-Radiotherapie (ISRT) den Therapiestandard dar. Bei persistierender Positronenemissionstomographie(PET)-Positivität ist eine Eskalation auf BEACOPPesc mit höherer Strahlendosis möglich. Intermediäre Stadien werden aktuell mit einer Kombination aus BEACOPPesc und ABVD behandelt, ergänzt durch eine Radiotherapie bei PET-positiven Residualbefunden. Mit diesen Konzepten lassen sich stadienübergreifend Heilungsraten von über 90

INTRODUCTION:Standard Ewing sarcoma treatment includes chemotherapy and local therapy. Previous studies found no average treatment effect of combined local therapy (radiotherapy and surgery) versus surgery alone, leaving it unclear which patients benefit from combined therapy. METHODS:We analysed patients with localized Ewing sarcoma from the EURO-E.W.I.N.G. 99 and Ewing 2008 trials. Using causal survival forests validated through repeated k-fold cross-validation, we predicted individualized treatment effects (ITEs) for 5-year event-free survival (5y EFS) comparing combined therapy to surgery alone. We developed a personalized treatment rule and evaluated ITE predictors using Shapley additive explanations analysis. RESULTS:Of 1501 patients, 719 received combination therapy and 782 surgery alone. Predicted ITEs showed substantial heterogeneity (range: -0.7-1.0 years). We found that 19.4% of patients derived clinically meaningful benefit (5y EFS increase ≥6 months) from combined therapy. In the quartile predicted to benefit least, hazards of any event were increased by 53% (HR 1.53, 95% CI 1.06-2.20, p = 0.02). Conversely, in the quartile predicted to benefit most, hazards were reduced by 40% (HR 0.60, 95% CI 0.42-0.85, p = 0.004). In patients undergoing combined treatment, surgical margin status was not associated with treatment benefit. A simulation analysis showed that applying our treatment strategy could improve EFS. DISCUSSION:Our predicted ITEs can help identify patients benefiting from combined therapy. The finding that patients with non-wide surgical margins did not benefit from combined therapy challenges current decision-making practices based on traditional subgroup analyses.

INTRODUCTION The German Hodgkin Study Group (GHSG) HD21 trial for adult patients with newly diagnosed advanced-stage classical Hodgkin lymphoma (AS-cHL) was designed to reduce treatment-related morbidity (TRMB) and improve efficacy by comparing the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) to the standard eBEACOPP protocol. Here, we report the final efficacy and safety including long-term progression-free survival (PFS), overall survival (OS), and late toxicity outcomes. METHODS This open-label, international, randomized phase III trial included adults aged 18-60 with newly diagnosed AS-cHL, randomized 1:1 to treatment with 4–6 cycles of eBEACOPP or BrECADD, guided by positron emission tomography after two cycles (PET2). The trial was registered at clinicaltrials.gov (NCT02661503) and conducted according to ICH-GCP guidelines. Co-primary objectives were reduction of TRMB and superiority of PFS with BrECADD vs. eBEACOPP, both of which were met previously. The final analysis focused on long-term PFS, overall survival (OS), and second primary malignancies (SPMs). Kaplan-Meier estimates and Cox regression were used for time-to-event analysis in the intention-to-treat (ITT) population. Additionally, we describe prognostic factors for PET2 response among baseline characteristics including metabolic tumor volume (MTV) and the prognostic value of international prognostic score (IPS) variables and MTV at baseline for PFS, respectively, in the BrECADD arm. Univariate logistic regressions were used to identify associations with interim PET response (p<=.001), which were then compared using multivariate analyses. RESULTS A total of 1,500 patients were enrolled between July 2016 and August 2020 across 233 sites in nine countries. Baseline demographics and disease characteristics were well balanced between arms. After 2 cycles of BrECADD, 235/664 patients (35%) with centrally reviewed PET2 were classified as PET-positive. ECOG > 0 (Odds Ratio [OR] 1.62, 95% CI 1.03-2.55) and higher MTV (OR 1.14 per 100 mL, 95% CI 1.06-1.22) at baseline were associated with positive PET after 2x BrECADD in multivariate analysis. Median follow-up for this final analysis was 60 months and seven new PFS-events occurred after the previous analysis at 48 months: Five in the eBEACOPP arm and two in the BrECADD arm. Confirming earlier analysis, the hazard ratio (HR) for PFS was 0.64 (95% CI 0.44–0.93) favoring BrECADD. The absolute 5-year PFS for BrECADD was 93.6% (95% CI 91.7–95.5) vs. 90.6% (95% CI 88.4-92.8) with eBEACOPP, with a particularly pronounced 5y PFS benefit in PET2-negative patients of 96.2% vs. 92.4% (HR 0.46, 95% CI 0.25–0.83;). Among the IPS variables, male sex (HR 2.68, CI 95% 1.37-5.27) and hemoglobin < 10.5 g/dL (HR 2.41, 95% CI 1.25-4.68) were associated with higher risk for PFS events in multivariate cox regression, whereas MTV at baseline in univariate cox regression was not (HR 0.95 per 100 mL, 95% CI 0.81-1.11). Salvage therapies were similar across treatment arms: most patients with progression or relapse received autologous stem cell transplantation (52/61 (82%) after eBEACOPP vs 29/38 (76%) after BrECADD). With four (two in each treatment group) new death events since the previous analysis, OS remained at 98% in both arms. The cumulative incidence of SPMs at 60 months was 2.1% after eBEACOPP and 2.8% after BrECADD, with differing patterns: more secondary MDS/AML occurred in the eBEACOPP arm (six vs. one), while more secondary NHL cases were observed in the BrECADD arm (two vs. eight). No new sMDS/AML events occurred beyond the primary analysis. CONCLUSION With 5 years follow-up, this analysis confirms the unprecedented primary cure-rate and long-term safety profile of BrECADD. While higher baseline lymphoma burden associates with incomplete remission at PET2, the risk for treatment failure seems mitigated through response-adaptation. Taken together, our results establish individualized BrECADD as a standard treatment option for adult patients with newly diagnosed AS-cHL.

Large B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%-40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.

Background. Ewing sarcoma (EwS) is a rare and highly malignant bone tumor primarily affecting children, adolescents, and young adults. The pelvis, trunk, and lower extremities are the most common sites, while EwS of the sacrum as a primary site is very rare, and only few studies focusing on this location are published. Due to the anatomical condition, local treatment is challenging in sacral malignancies. We analyzed factors that might influence the outcome of patients suffering from sacral EwS. Methods. We retrospectively analyzed data of the GPOH EURO-E.W.I.N.G 99 trial and the EWING 2008 trial, with a cohort of 124 patients with localized or metastatic sacral EwS. The study endpoints were overall survival (OS) and event-free survival (EFS). OS and EFS were calculated using the Kaplan–Meier method, and univariate comparisons were estimated using the log-rank test. Hazard ratios (HRs) with respective 95% confidence intervals (CIs) were estimated in a multivariable Cox regression model. Results. The presence of metastases (3y-EFS: 0.33 vs. 0.68; P<0.001; HR = 3.4, 95% CI 1.7 to 6.6; 3y-OS: 0.48 vs. 0.85; P<0.001; HR = 4.23, 95% CI 1.8 to 9.7), large tumor volume (≥200 ml) (3y-EFS: 0.36 vs. 0.69; P=0.02; HR = 2.1, 95% CI 1.1 to 4.0; 3y-OS: 0.42 vs. 0.73; P=0.04; HR = 2.1, 95% CI 1.03 to 4.5), and age ≥18 years (3y-EFS: 0.41 vs. 0.60; P=0.02; HR = 2.6, 95% CI 1.3 to 5.2; 3y-OS: 0.294 vs. 0.59; P=0.01; HR = 2.92, 95% CI 1.29 to 6.6) were revealed as adverse prognostic factors. Conclusion. Young age seems to positively influence patients` survival, especially in patients with primary metastatic disease. In this context, our results support other studies, stating that older age has a negative impact on survival. Tumor volume, metastases, and the type of local therapy modality have an impact on the outcome of sacral EwS. Level of evidence: Level 2. This trial is registered with NCT00020566 and NCT00987636.

Purpose:Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS. Methods and Materials:The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S&RT group) and/or RT (RT group). EFS and OS were analyzed with uni- and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response. Results:S&RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose ≤ 53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose ≥ 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S&RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 (P = .42) and in the RT group 52.9%, 62.5%, and 70.3% (P = .63), respectively. Multivariable Cox regression revealed age ≥ 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S&RT group (sex, P = .96; histologic response, P = .07; tumor volume, P = .50; dose, P = .10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P = .15; age, P = .08; sex, P = .40). Conclusions:In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias.

BACKGROUND:Local treatment is a crucial element in the standard of care for Ewing sarcoma (EWS). While systemic treatment is improved in randomised clinical trials, local treatment modalities are discussed controversially. We analysed the association between local therapy and event-free survival (EFS), overall survival (OS), and local recurrence (LR) in prospectively collected data of patients with localised EWS. PATIENTS AND METHODS:We analysed data from the international Ewing 2008 study registered between 2009 and 2019 in 117 centres. After induction chemotherapy, patients received surgery, radiotherapy, or a combination thereof. We performed Cox regression, conducted propensity score-weighted sensitivity analysis, and performed subgroup analyses. Hazard ratios (HRs) and 95% confidence intervals are reported. RESULTS:We included 863 patients with localised EWS (surgery alone: 331, combination therapy: 358, definitive radiotherapy: 174). In patients treated with combination therapy compared to surgery alone, EFS HR was 0.84 (0.57-1.24; p = 0.38), OS HR was 0.84 (0.57-1.23; p = 0.41), and LR HR was 0.58 (0.26-1.31; p = 0.19). Hazards of any event were increased in patients treated with definitive radiotherapy compared to surgery only, HR 1.53 (1.02-2.31; p = 0.04). Patients with poor responses to chemotherapy benefitted from combination therapy over definitive surgery with an EFS HR 0.49 (0.27-0.89; p = 0.02). Patients with pelvic tumours benefitted from combination therapy over surgery only regarding LR, HR 0.12 (0.02-0.72; p = 0.02). CONCLUSION:Patients with poor responses to chemotherapy benefitted from radiotherapy added to surgery. In the whole group, radiotherapy alone as opposed to surgery alone increased the hazards of any event.

1 Lancet Oncol 2012;13(12):1250-1259. 2 Lancet Haematol 2021;8(4):e267-e277.

The HD 16 and 17 trials by the German Hodgkin Study Group (GHSG) have evaluated the use of consolidative radiotherapy (RT) in early-favorable and -unfavorable stage Hodgkin lymphoma (HL), respectively (1, 2). Quality of RT planning and execution is pivotal for treatment outcome in HL with protocol violations jeopardizing prognosis (3). Consequently, the present work aims at a decisive analysis of quality and dosimetry in the modern era.Random samples of 100 involved-field RT (IFRT) plans in HD16 and 176 plans in HD17 (134 involved-node RT (INRT) and 42 IFRT) were selected for analysis. Evaluation was performed systematically by the reference radiation oncology panel using pre-chemotherapy imaging, recommendation by the reference radiation oncology and RT planning imaging and graded as "correct", "minor" or "major deviation", respectively. RT doses to the target volume and organs at risks (OAR) were analyzed using dose-volume histograms.Median RT doses were 20 Gy (19.8 Gy-21.6 Gy) in HD16 and 30 Gy in HD17 (IFRT: 18-30.6 Gy, INRT: 14 Gy-40 Gy). Overall, 84.0%, 69.0%, and 76.1% of RT series in HD16, the IFRT-group of HD17 and the INRT-group of HD17, respectively, were planned correctly. The main reason for major deviation was an insufficient coverage of an involved region (11 %-14.3 %). There was no significant difference in quality between IFRT and INRT in HD17 (p = 0.418 for any deviations; p = 0.466 for major deviations). In comparison to previous GHSG studies in the respective stages, a significant increase in correct RT-series (p<0.001) and decrease in major deviations (p<0.001) occurred. However, doses to OAR varied individually with median values of 4.3 Gy (0.2 Gy-9.2 Gy), 4.7 Gy (0.2 Gy-15.2 Gy) and 3.8 Gy (0.0 Gy-16.0 Gy) for mean doses to the right lung, left lung and heart in HD16, respectively. Correspondingly, values were 9.8 Gy (0.3 Gy-20.0 Gy), 10.5 Gy (0.2 Gy-26.5 Gy) and 13.1 Gy (0.5 Gy-30.4 Gy) for mean doses to the right lung, left lung and heart in HD17, respectively. The size of the planning target volume decreased significantly with INRT compared to IFRT (median values: 1163.1 ml vs. 1464.3 ml; p = 0.043). However, only some OAR-parameters (V25 of the right and left lung, respectively, thyroid and spinal cord) showed significant differences between INRT and IFRT in HD17. The use of intensity-modulated techniques in HD 17 resulted in an increase in V5 and V10 of the lungs with a concomitant decrease in V20-V30.Quality of RT in the planning and treatment of HL has improved significantly with the latest GHSG study generation. Future analyses will focus on a further individualization of treatment fields.

The objective was to assess the cost-effectiveness of staging PET/CT in early-stage follicular lymphoma (FL) from the Canadian health-care system perspective. Methods: The study population was FL patients staged as early-stage using conventional CT imaging and planned for curative-intent radiation therapy (RT). A decision analytic model simulated the management after adding staging PET/CT versus using staging CT alone. In the no-PET/CT strategy, all patients proceeded to curative-intent RT as planned. In the PET/CT strategy, PET/CT information could result in an increased RT volume, switching to a noncurative approach, or no change in RT treatment as planned. The subsequent disease course was described using a state-transition cohort model over a 30-y time horizon. Diagnostic characteristics, probabilities, utilities, and costs were derived from the literature. Baseline analysis was performed using quality-adjusted life years (QALYs), costs (2019 Canadian dollars), and the incremental cost-effectiveness ratio. Deterministic sensitivity analyses were conducted, evaluating net monetary benefit at a willingness-to-pay threshold of $100,000/QALY. Probabilistic sensitivity analysis using 10,000 simulations was performed. Costs and QALYs were discounted at a rate of 1.5%. Results: In the reference case scenario, staging PET/CT was the dominant strategy, resulting in an average lifetime cost saving of $3,165 and a gain of 0.32 QALYs. In deterministic sensitivity analyses, the PET/CT strategy remained the preferred strategy for all scenarios supported by available data. In probabilistic sensitivity analysis, the PET/CT strategy was strongly dominant in 77% of simulations (i.e., reduced cost and increased QALYs) and was cost-effective in 89% of simulations (i.e., either saved costs or had an incremental cost-effectiveness ratio below $100,000/QALY). Conclusion: Our analysis showed that the use of PET/CT to stage early-stage FL patients reduces cost and improves QALYs. Patients with early-stage FL should undergo PET/CT before curative-intent RT.

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.

PurposeThe 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 MaterialsBetween 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).ResultsThere 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.ConclusionsPET-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.

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/m(2) intravenous cyclophosphamide on day 1, 35 mg/m(2) intravenous doxorubicin on day 1, 200 mg/m(2) intravenous etoposide on days 1-3, 100 mg/m(2) oral procarbazine on days 1-7, 40 mg/m(2) oral prednisone on days 1-14, 1.4 mg/m(2) intravenous vincristine on day 8 [maximum dose of 2 mg per cycle], and 10 mg/m(2) intravenous bleomycin on day 8; ABVD consisted of 25 mg/m(2) intravenous doxorubicin, 10 mg/m(2) intravenous bleomycin, 6 mg/m(2) intravenous vinblastine, and 375 mg/m(2) 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 betweengroup 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 radiotherapyassociated 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. Copyright (c) 2020 Elsevier Ltd. All rights reserved.