Impact of individualized treatment on recovery from fatigue and return to work in survivors of advanced-stage Hodgkin's lymphoma: results from the randomized international GHSG HD18 trial.

BACKGROUND: Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin's lymphoma (HL). The GHSG HD18 trial established treatment de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W). PATIENTS AND METHODS: Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables. RESULTS: HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F [hazard ratio (HR) 1.41, P = 0.008] and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL. CONCLUSIONS: Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL.

Prognostic impact of gross tumor volume during radical radiochemotherapy of locally advanced non-small cell lung cancer-results from the NCT03055715 multicenter cohort study of the Young DEGRO Trial Group.

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 < 0.001). Median overall survival (OS) was 18.8 months with a median of 22.1, 20.9, and 12.6 months for patients with high, intermediate, and low GTV before RT. Considering all patients, in one survival model of overall mortality, GTV2 (2.75 (1.12-6.75, 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.

Radiation treatment of hemato-oncological patients in times of the COVID-19 pandemic : Expert recommendations from the radiation oncology panels of the German Hodgkin Study Group and the German Lymphoma Alliance.

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.

Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18.

Background: Bone marrow (BM) involvement defines advanced-stage Hodgkin lymphoma and thus has impact on the assignment to treatment. Our aim was to evaluate whether the established BM biopsy may be omitted in patients if 18F-fluorodeoxyglucose positron emission tomography (PET) scanning is carried out during staging. Patients and methods: Our analysis set consisted of 832 Hodgkin lymphoma patients from the German Hodgkin Study Group trials HD16, HD17, and HD18 who underwent both PET scanning and BM biopsy before treatment. All PET studies were centrally reviewed and BM was categorized as showing focal involvement or not. Results: Taking BM biopsy as reference standard, baseline PET showed a negative predictive value of 99.9% [95% confidence interval (CI) 99.2% to 100%] with true-negative results in 702 of 703 cases. The sensitivity of PET for detecting BM involvement was 95.0% (95% CI 75.1% to 99.9%) as it could identify 19 out of 20 patients with positive BM biopsy. Moreover, PET found 110 additional subjects with focal BM lesions who would have been considered negative by biopsy. Conclusions: When compared with BM biopsy, PET was able to detect focal BM lesions in a large number of additional patients. This indicates that conventional BM biopsy may substantially underestimate the actual incidence of BM involvement. Given the high negative predictive value, baseline PET scanning can safely be used to exclude BM involvement in Hodgkin lymphoma. BM biopsy should be considered only in such patients in whom PET-detected lesions lead to a change of treatment protocol. Registered trials: The trials included in this analysis were registered at ClinicalTrials.gov: HD16-NCT00736320, HD17-NCT01356680, and HD18-NCT00515554.

[Image-guided, minimally invasive surgery and other local therapeutic procedures for primary liver tumors]. / Bildgestützte minimal-invasive Chirurgie und andere lokaltherapeutische Verfahren bei primären Lebertumoren.

BACKGROUND: The incidence of primary liver tumors is rising. Modern minimally invasive, image-guided procedures offer a potentially curative therapy option. OBJECTIVE: The aim of this study was to evaluate the multitude of image-guided minimally invasive procedures concerning their evidence-based effect on local tumor control and overall survival. MATERIAL AND METHODS: A systematic search of MEDLINE focused on hepatocellular cancer, minimally invasive treatment, local ablative therapy, therapeutic stratification and comparative studies was performed. RESULTS: The level of evidence varied greatly depending on the procedure used. The highest quality evidence including prospective randomized studies was found for radiofrequency ablation (RFA) of hepatocellular cancer. The RFA is superior with respect to local tumor control and overall survival in comparison to other ablative procedures. Prospective randomized studies comparing surgery and RFA showed diverging and contradictory results. Microwave ablation and robotic stereotactic irradiation showed sufficient potential in retrospective studies in comparison to RFA and surgery in order to confirm the techniques in randomized studies. There is only anecdotal evidence concerning high intensity focused ultrasound (HIFU) and irreversible electroporation. Percutaneous ethanol injection (PEI), cryoablation and laser-induced thermal therapy (LITT) were inferior techniques to RFA in most studies. CONCLUSION: Minimally invasive resection and local ablative therapies based on structured imaging and image reporting can improve the prognosis of patients with hepatocellular cancer even in patients that exceed the BCLC 0/A stage.

New quality assurance program integrating "modern radiotherapy" within the German Hodgkin Study Group.

INTRODUCTION: Field design changed substantially from extended-field RT (EF-RT) to involved-field RT (IF-RT) and now to involved-node RT (IN-RT) and involved-site RT (IS-RT) as well as treatment techniques in radiotherapy (RT) of Hodgkin's lymphoma (HL). The purpose of this article is to demonstrate the establishment of a quality assurance program (QAP) including modern RT techniques and field designs within the German Hodgkin Study Group (GHSG). METHODS: In the era of modern conformal RT, this QAP had to be fundamentally adapted and a new evaluation process has been intensively discussed by the radiotherapeutic expert panel of the GHSG. RESULTS: The expert panel developed guidelines and criteria to analyse "modern" field designs and treatment techniques. This work is based on a dataset of 11 patients treated within the sixth study generation (HD16-17). CONCLUSION: To develop a QAP of "modern RT", the expert panel defined criteria for analysing current RT procedures. The consensus of a modified QAP in ongoing and future trials is presented. With this schedule, the QAP of the GHSG could serve as a model for other study groups.

Checkpoint inhibitors and radiation treatment in Hodgkin's lymphoma : New study concepts of the German Hodgkin Study Group.

BACKGROUND: Patients with classical Hodgkin's lymphoma (cHL) have a good prognosis even in advanced stages. However, combined chemo- and radiotherapy, as the standard of care, is also associated with treatment-related toxicities such as organ damage, secondary neoplasias, infertility, or fatigue and long-term fatigue. Many patients suffer from this burden although their cHL was cured. Therefore, the efficacy of immune checkpoint inhibitors like anti-PD1/PD-L1 antibodies in the treatment of solid cancers and also in HL offers new options. A remarkable and durable response rate with a favorable toxicity profile was observed in heavily pretreated cHL patients. METHODS: Planning to perform prospective randomized clinical trials in the content of radio-immune treatment in patients with Hodgkin's lymphoma (HL), we transferred the results of preliminary clinical studies and basic research in clinical relevant study concepts. RESULTS: Based on these promising early phase trial data, the German Hodgkin Study Group (GHSG) will investigate innovative treatment regimens in upcoming phase II trials. CONCLUSION: The therapeutic efficacy and potential synergies of anti-PD1 antibodies in combination with chemo- or radiotherapy will be investigated in various settings of HL.

Quality control of involved field radiotherapy in the HD 13 and HD 14 trials : Report of the radiotherapy panel of the German Hodgkin Study Group (GHSG).

INTRODUCTION: 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. METHODS: 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. RESULTS: 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 %). CONCLUSION: 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.

Concordance in the interpretation of PET after chemotherapy in advanced stage Hodgkin lymphoma.

UNLABELLED: The aim was to analyze the degree of agreement between the central review panel and the local PET interpretation within the HD15 trial and its impact on subsequent treatment and progression free survival. PATIENTS, METHODS: The analysis set consisted of 739 patients with residues ≥ 2.5 cm after 6 or 8 cycles of BEACOPPesc from the HD15 trial performed by the German Hodgkin Study Group. The recommendation for or against further radiotherapy was based on the central [(18)F]FDG-PET interpretation. Central PET interpretation was compared to the local PET interpretation and concordance was measured using Cohen's Kappa coefficient. Prognostic impact of the analysis of concordance between local and central PET interpretations was evaluated using progression free survival (PFS); groups were compared with the log rank test. RESULTS: The central panel rated 548 of 739 patients (74%) as PET negative. Of these, 513 were also rated as PET negative in the local PET interpretation. PET positivity was seen by central reviewers in the remaining 191 patients (26%), in concordance with local reviewers in 155 cases. Even though substantial agreement was found (Cohen's Kappa 0.81), the interpretation of the central PET review panel led to a different therapeutic recommendation in 71/739 (10%) patients. PFS was equally high in groups in which the therapeutic regime had been changed on the basis of the central panel decision. CONCLUSION: High concordance is found between local and central reviewers with regard to PET interpretation in residual tissue after intense chemotherapy. The existence of the central PET review panel allows the identification of additional patients as PET negative so that radiotherapy can be safely omitted (35 of 548 patients = 4.7%).

Quality control of involved-field radiotherapy for patients with early stage Hodgkin's lymphoma based on a central prospective review. Comparison of the results between two study generations of the German Hodgkin Study Group.

PURPOSE: Based on experience in trials HD10 and HD11 (1998-2003), the radiotherapy reference center of the German Hodgkin Study Group (GHSG) continued their central prospective radiation oncological review in trials HD13 and HD14. The purpose of this analysis was to identify the impact of this procedure on radiotherapeutic management and to compare findings with former trials. METHODS: Between 2003 and 2009, 1,710 patients were enrolled in the HD13 trial (early favorable stages) and 2,039 patients in the HD14 trial (early unfavorable stages). All patients received a total of 30 Gy involved-field (IF) radiotherapy within a combined modality approach. RESULTS: For patients in HD13, there was a correction of disease involvement in 847/1,518 patients (56%), and for patients in HD14 in 1,370/1,905 patients (72%). Most discrepancies were observed in the lower mediastinum (19.2%), infraclavicular (31.7%), upper cervical (12.7%), and supraclavicular (10.8%) lymph nodes. This resulted in a change of disease stage in 241 (7%) patients and a shift into another study protocol in 66 (2%) patients. Due to the incorrect lymph node documentation of the participating study centers, the IF radiotherapy volume had to be enlarged in 1,063/3,423 patients (31%) and reduced in 244/3,423 patients (7.1%). These findings are comparable to the results of the quality control in the trials HD10 and HD11 (2,611 patients reviewed). CONCLUSION: Central review of the diagnostic imaging and clinical findings of Hodgkin's lymphoma patients shows a considerable number of discrepancies compared with the local evaluation. Thus, meticulous evaluation of all imaging information in close collaboration between the radiation oncologist and diagnostic radiologist is mandatory.

Acute bacterial otitis externa: efficacy and safety of topical treatment with an antibiotic ear drop formulation in comparison to glycerol treatment.

OBJECTIVES: To demonstrate the efficacy and safety of an antibiotic ear drop formulation combining polymyxin B sulfate, neomycin sulfate and gramicidin (PS) in patients with acute bacterial otitis externa (AOE). The combination was compared to glycerol ear drops, a non-pharmacologic treatment of AOE. METHODS: An active controlled, double-blind, randomized, parallel group, multicenter clinical trial study design was performed in ear, nose and throat (ENT) practices with a planned interim analysis for sample size adaptation. In total, 244 patients aged 19-84 with no previous episode of otitis externa within the last year were randomized to receive either PS or glycerol ear drops thrice daily for 10 ± 2 days. OUTCOME MEASURES: Absolute change in the clinical symptom score (CSS) (with subscores redness, swelling, pain, and secretion) from Day 1 to 4 was measured. As second endpoints, absolute change in CSS, individual subscores, pain perception measured on a visual analog scale (VAS) and intake of paracetamol 500 mg tablets were noted. Moreover, patient's assessment of efficacy at Day 10 and the frequency and type of adverse events were noted. RESULTS: On Day 4, the CSS showed a clear advantage for the PS group over the glycerol group, being lower by 0.6 (p < 0.03); the clinical outcome was even more pronounced after 10 days (p = 0.006). The swelling subscore showed a statistically significant difference favoring the PS treatment group in Days 1-4 (p = 0.01) and Days 1-10 (p = 0.003). More PS- than glycerol-receiving patients rated the efficacy as good (glycerol: 32%; PS: 36%) or very good (glycerol: 38%; PS: 48%). Males, patients with AOE for >2 days and those with positive microbiologic findings profited most from PS therapy. CONCLUSION: This study proves that PS is an effective and well-tolerated drug, showing results superior to glycerol, especially in patients with a longer pre-existing condition before therapy. The absence of a group treated with another established antibiotic is a limitation of this trial.