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Design and rationale of the randomized trial of comprehensive lifestyle modification, optimal pharmacological treatment and utilizing PET imaging for quantifying and managing stable coronary artery disease (the CENTURY study).
Kitkungvan, D, Johnson, NP, Kirkeeide, R, Haynie, M, Carter, C, Patel, MB, Bui, L, Madjid, M, Mendoza, P, Roby, AE, et al
American heart journal. 2021;:135-146
Abstract
BACKGROUND The literature reports no randomized trial in chronic coronary artery disease (CAD) of a comprehensive management strategy integrating intense lifestyle management, maximal medical treatment to specific goals and high precision quantitative cardiac positron emission tomography (PET) for identifying high mortality risk patients needing essential invasive procedures. We hypothesize that this comprehensive strategy achieves greater risk factor reduction, lower major adverse cardiovascular events and fewer invasive procedures than standard practice. METHODS The CENTURY Study (NCT00756379) is a randomized-controlled-trial study in patients with stable or at high risk for CAD. Patients are randomized to standard of care (Standard group) or intense comprehensive lifestyle-medical treatment to targets and PET guided interventions (Comprehensive group). Comprehensive Group patients are regularly consulted by the CENTURY team implementing diet/lifestyle/exercise program and medical treatment to target risk modification. Cardiac PET at baseline, 24-, and 60-months quantify the physiologic severity of CAD and guide interventions in the Comprehensive group while patients and referring physicians of the Standard group are blinded to PET results. The primary end-point is the CENTURY risk score reduction during 5 years follow-up. The secondary endpoint is a composite of death, non-fatal myocardial infarction, stroke, and coronary revascularization. CONCLUSIONS The CENTURY Study is the first study in stable CAD to test the incremental benefit of a comprehensive strategy integrating intense lifestyle modification, medical treatment to specific goals, and high-precision quantitative myocardial perfusion imaging to guide revascularization. A total of 1028 patients have been randomized, and the 5 years follow-up will conclude in 2022.
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Effect of 26 Weeks of Liraglutide Treatment on Coronary Artery Inflammation in Type 2 Diabetes Quantified by [64Cu]Cu-DOTATATE PET/CT: Results from the LIRAFLAME Trial.
Jensen, JK, Zobel, EH, von Scholten, BJ, Rotbain Curovic, V, Hansen, TW, Rossing, P, Kjaer, A, Ripa, RS
Frontiers in endocrinology. 2021;:790405
Abstract
BACKGROUND Quantification of coronary artery inflammation and atherosclerosis remains a challenge in high-risk individuals. In this study we sought to investigate if the glucagon like peptide-1 receptor agonist liraglutide has a direct anti-inflammatory effect in the coronary arteries using positron emission tomography (PET) with a radioactive tracer targeting activated macrophages in the vessel-wall. METHODS Thirty randomly selected participants with type 2 diabetes from the placebo-controlled trial LIRAFLAME were enrolled in this sub-study. Participants were, prior to enrollment in this sub-study, randomized to either treatment with daily liraglutide (n=15) or placebo (n=15). Both groups underwent a combined [64Cu]Cu-DOTATATE positron emission tomography and computed tomography scan of the heart at baseline and after 26 weeks of treatment. Coronary artery uptake of [64Cu]Cu-DOTATATE were measured as maximum standardized uptake values (SUVmax); and means of the maximum values (mSUVmax), both values were calculated at the level of each participant and each individual coronary-segment. RESULTS SUVmax and mSUVmax values decreased significantly in the liraglutide group both at the participant level (SUVmax: p=0.013; mSUVmax: p=0.004) and at the coronary-segment level (SUVmax: p=0.001; mSUVmax: p<0.0001). No change was observed in the placebo group neither at the participant level (SUVmax: p=0.69; mSUVmax: p=0.67) or at the coronary-segment level (SUVmax: p=0.49; mSUVmax: p=0.30). When comparing the mean change in uptake values between the two groups at both the participant level (SUVmax: p=0.076; mSUVmax: p=0.077) and the coronary segment level (SUVmax: p=0.13; mSUVmax: p=0.11) a borderline significant difference was observed. Baseline SUVmax [64Cu]Cu-DOTATATE uptake values showed a weak positive correlation with the inflammatory biomarker high-sensitivity c-reactive protein (τ =0.26, p=0.045). CONCLUSION Liraglutide treatment for 26-weeks caused a significant reduction in [64Cu]Cu-DOTATATE uptake in the coronary arteries whereas this was not seen in the placebo treated group. In addition, [64Cu]Cu-DOTATATE PET/CT as a marker of coronary inflammation correlated with the systemic inflammation marker hs-CRP.
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Early Response to First-Line Anti-PD-1 Treatment in Hodgkin Lymphoma: A PET-Based Analysis from the Prospective, Randomized Phase II NIVAHL Trial.
Voltin, CA, Mettler, J, van Heek, L, Goergen, H, Müller, H, Baues, C, Keller, U, Meissner, J, Trautmann-Grill, K, Kerkhoff, A, et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2021;(2):402-407
Abstract
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.
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Randomized Phase II Study of PET Response-Adapted Combined Modality Therapy for Esophageal Cancer: Mature Results of the CALGB 80803 (Alliance) Trial.
Goodman, KA, Ou, FS, Hall, NC, Bekaii-Saab, T, Fruth, B, Twohy, E, Meyers, MO, Boffa, DJ, Mitchell, K, Frankel, WL, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2021;(25):2803-2815
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PURPOSE To evaluate the use of early assessment of chemotherapy responsiveness by positron emission tomography (PET) imaging to tailor therapy in patients with esophageal and esophagogastric junction adenocarcinoma. METHODS After baseline PET, patients were randomly assigned to an induction chemotherapy regimen: modified oxaliplatin, leucovorin, and fluorouracil (FOLFOX) or carboplatin-paclitaxel (CP). Repeat PET was performed after induction; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders (< 35% decrease in SUV) crossed over to the alternative chemotherapy during chemoradiation (50.4 Gy/28 fractions). PET responders (≥ 35% decrease in SUV) continued on the same chemotherapy during chemoradiation. Patients underwent surgery at 6 weeks postchemoradiation. Primary end point was pathologic complete response (pCR) rate in nonresponders after switching chemotherapy. RESULTS Two hundred forty-one eligible patients received Protocol treatment, of whom 225 had an evaluable repeat PET. The pCR rates for PET nonresponders after induction FOLFOX who crossed over to CP (n = 39) or after induction CP who changed to FOLFOX (n = 50) was 18.0% (95% CI, 7.5 to 33.5) and 20% (95% CI, 10 to 33.7), respectively. The pCR rate in responders who received induction FOLFOX was 40.3% (95% CI, 28.9 to 52.5) and 14.1% (95% CI, 6.6 to 25.0) in responders to CP. With a median follow-up of 5.2 years, median overall survival was 48.8 months (95% CI, 33.2 months to not estimable) for PET responders and 27.4 months (95% CI, 19.4 months to not estimable) for nonresponders. For induction FOLFOX patients who were PET responders, median survival was not reached. CONCLUSION Early response assessment using PET imaging as a biomarker to individualize therapy for patients with esophageal and esophagogastric junction adenocarcinoma was effective, improving pCR rates in PET nonresponders. PET responders to induction FOLFOX who continued on FOLFOX during chemoradiation achieved a promising 5-year overall survival of 53%.
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Comparison of 18F-FDG PET-MR and fecal biomarkers in the assessment of disease activity in patients with ulcerative colitis.
Li, Y, Khamou, M, Schaarschmidt, BM, Umutlu, L, Forsting, M, Demircioglu, A, Haubold, J, Koch, AK, Bruckmann, NM, Sawicki, LM, et al
The British journal of radiology. 2020;(1112):20200167
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OBJECTIVE To compare the diagnostic performance of fecal biomarkers and 18F-fludeoxyglucose (18F-FDG) positron emmision tomography-MR (PET-MR) in the assessment of disease activity in patients with ulcerative colitis. METHODS This study was conducted under the framework of a single-center clinical trial (clinicaltrials.gov [NCT03781284]). N = 50 participants were enrolled. Fecal samples were collected before bowel preparation. All patients underwent whole-body 18F-FDG PET-MR followed by ileocolonoscopy within 24 h. Diagnostic performance of five fecal biomarkers (calprotectin, lactoferrin, polymorphonuclear leukocyte elastase, S100A12 and eosinophil-derived neurotoxin), MR morphological parameters (MRmorph), diffusion-weighted imaging and PET in detecting active disease determined by Rachmilewitz endoscopic activity index (EAI) were evaluated and compared with each other. Correlations between fecal biomarkers, PET and endoscopy were calculated. RESULTS According to EAI, n = 38 patients presented with endoscopically active disease (16 mild, 19 moderate and 3 severe). All five biomarkers, PET and MRmorph could differentiate endoscopically active disease from endoscopic remission without significant difference regarding their operating characteristics (accuracies between 0.673 for calprotectin and 0.898 for lactoferrin). In predicting endoscopically moderate to severe disease, PET showed the highest diagnostic performance (accuracy = 0.857) compared to calprotectin and lactoferrin (accuracy = 0.633 and 0.735). PET had also the strongest correlation with endoscopy (ρ = 0.685, p < 0.001), while within fecal biomarkers the levels of lactoferrin and eosinophil-derived neurotoxin correlated significantly with EAI (ρ = 0.423 and 0.528, both p < 0.05). CONCLUSION Both fecal biomarkers and PET-MR were excellent non-invasive diagnostic tools in the assessment of disease activity in ulcerative colitis. ADVANCES IN KNOWLEDGE Both fecal biomarkers and PET-MR parameters are able to predict endoscopically active disease with comparable diagnostic performance. PET had the highest correlation with endoscopy and outperformed fecal biomarkers in differentiating moderate to severe from mild disease.
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The INTERNET STUDY: A phase II study of everolimus in patients with fluorodeoxyglucose (18 F) positron-emission tomography positive intermediate grade pancreatic neuroendocrine tumors.
Lung, MS, Hicks, RJ, Pavlakis, N, Link, E, Jefford, M, Thomson, B, Wyld, DK, Liauw, W, Akhurst, T, Kuru, N, et al
Asia-Pacific journal of clinical oncology. 2020;(3):150-157
Abstract
AIMS: This multicenter phase II trial evaluates the efficacy of everolimus in poor prognosis grade 2 (G2) pancreatic neuroendocrine tumors (PNETs), defined by 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) avidity. FDG-PET avidity in NETs is associated with a significantly higher risk of death, outperforming Ki-67 index or liver metastases as a poor prognostic factor. We hypothesized that everolimus has efficacy in patients with FDG-PET-avid G2 PNETs and prospectively evaluated progression-free survival (PFS) and response in the first-line setting. METHODS Patients with FDG-PET-avid G2 advanced PNET received everolimus 10 mg daily until disease progression. Patients were staged every 12 weeks with CT/MRI and FDG-PET and every 24 weeks with Gallium 68 (68Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) PET. The primary endpoint was PFS at 6 months. Overall survival rate, PET/structural imaging response and toxicity were also measured. RESULTS Nine patients were accrued from December 2012 to February 2015. Median treatment duration was 13.8 months. The estimated PFS rate at 6 months was 78%. The best response on CT/MRI was stable disease in nine patients (100%) and partial response on FDG-PET in five patients (55.5%). Treatment-related adverse effects were consistent with previous studies of everolimus. CONCLUSION Everolimus is active with prolonged disease control in poor prognosis FDG-avid G2 PNETs. Treatment individualization based on functional imaging warrants further evaluation.
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Quantitative myocardial perfusion positron emission tomography and caffeine revisited with new insights on major adverse cardiovascular events and coronary flow capacity.
Kitkungvan, D, Bui, L, Johnson, NP, Patel, MB, Roby, AE, Vejpongsa, P, Babar, AK, Madjid, M, Nacimbene, A, Kumar, S, et al
European heart journal. Cardiovascular Imaging. 2019;(7):751-762
Abstract
AIMS: To evaluate effects of caffeine on quantitative myocardial perfusion by positron emission tomography (PET) and associated major adverse cardiovascular events (MACE). METHODS AND RESULTS Serum caffeine was measured for all 6087 PETs with 328 positive results (5.4%). Paired caffeine positive/negative PETs (84 patients for dipyridamole with median caffeine 1.6 mg/L, and additional 25 volunteers for regadenoson with median caffeine 7.4 mg/L) were compared for quantitative perfusion. Multivariate regression analysis for associations among caffeine, clinical/imaging variables, predicted caffeine probability was performed. MACEs were followed up to 9 years after PETs. For caffeine vs. no caffeine, respectively, stress flow was 1.74 ± 0.55 vs. 2.14 ± 0.53 for dipyridamole and 1.82 ± 0.61 vs. 2.33 ± 0.49 mL/min/g for regadenoson, and coronary flow reserve (CFR) was 2.26 ± 0.67 vs. 2.67 ± 0.72 for dipyridamole and 1.84 ± 0.33 vs. 2.31 ± 0.41 for regadenoson (all P < 0.001). Subjects were reclassified from high-risk CFR ≤2.0 with caffeine to low-risk CFR >2.0 without caffeine in 66.7% and 80% of dipyridamole and regadenoson caffeine-no-caffeine pairs, respectively. While relative images showed no differences, caffeine significantly altered coronary flow capacity (CFC) to false negative and false positive severity in 2.1% and 5.5% of the 328 caffeine positives, respectively (0.1% and 0.3% of 6087 PETs) but without change in severity guided management in most patients (92.4% of 328 caffeine or 99.6% of total 6087 PETs). CONCLUSION Even low serum caffeine levels reduce quantitative perfusion during vasodilatory stress with false positive or false negative results minimized by empathic instruction, CFC analysis or repeat PET after strict caffeine abstention for definitive individualized risk stratification and management.
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Impact of 18F-Fluciclovine PET on Target Volume Definition for Postprostatectomy Salvage Radiotherapy: Initial Findings from a Randomized Trial.
Jani, AB, Schreibmann, E, Rossi, PJ, Shelton, J, Godette, K, Nieh, P, Master, VA, Kucuk, O, Goodman, M, Halkar, R, et al
Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017;(3):412-418
Abstract
The purpose of this study was to evaluate the role of the synthetic amino acid PET radiotracer 18F-fluciclovine in modifying the defined clinical and treatment-planning target volumes in postprostatectomy patients undergoing salvage radiotherapy and to evaluate the resulting dosimetric consequences to surrounding organs at risk. Methods: Ninety-six patients were enrolled in a randomized, prospective intention-to-treat clinical trial for potential salvage radiotherapy for recurrent prostate cancer after prostatectomy. The initial treatment plan was based on the results from conventional abdominopelvic CT and MRI. The 45 patients in the experimental arm also underwent abdominopelvic 18F-fluciclovine PET/CT, and the images were registered with the conventional images to determine whether the results would modify the initial treatment plan. The 51 patients in the control arm did not undergo 18F-fluciclovine PET/CT. For each patient, the clinical and treatment-planning target volumes that would have been treated before 18F-fluciclovine registration were compared with those after registration. For organs at risk (rectum, bladder, and penile bulb), the volumes receiving 40 Gy and 65 Gy before registration were compared with those after registration. Statistical comparisons were made using the paired t test. Acute genitourinary and gastrointestinal toxicity as defined by the Radiation Therapy Oncology Group was compared between the control and experimental arms using the χ2 test. Results: In 24 cases, radiotherapy was planned to a clinical target volume consisting of the prostate bed alone (CTV) (64.8-66.6 Gy). In 21 cases, radiotherapy was planned to a clinical target volume consisting of the pelvis (CTV1) (45.0 Gy) followed by a boost to the prostate bed (CTV2) (19.8-25.2 Gy). In each case, the respective treatment-planning target volume expansion (PTV, PTV1, or PTV2) was 0.8 cm (0.6 cm posterior). With the exception of PTV2, all postregistration volumes were significantly larger than the corresponding preregistration volumes. Analysis of the rectum, bladder, and penile bulb volumes receiving 40 Gy and 60 Gy demonstrated that only the penile bulb volumes were significantly higher after registration. No significant differences in acute genitourinary or gastrointestinal toxicity were observed. Conclusion: Including information from 18F-fluciclovine PET in the treatment-planning process led to significant differences in the defined target volume, with higher doses to the penile bulb but no significant differences in rectal or bladder dose or in acute genitourinary or gastrointestinal toxicity. Longer follow-up is needed to determine the impact of 18F-fluciclovine PET on cancer control and late toxicity endpoints.
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Uniform FDG-PET guided GRAdient Dose prEscription to reduce late Radiation Toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma.
van den Bosch, S, Dijkema, T, Kunze-Busch, MC, Terhaard, CH, Raaijmakers, CP, Doornaert, PA, Hoebers, FJ, Vergeer, MR, Kreike, B, Wijers, OB, et al
BMC cancer. 2017;(1):208
Abstract
BACKGROUND In definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called 'elective dose' in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary. Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment. METHODS UPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial. Patients to be treated with definitive radiation therapy for a newly diagnosed stage T2-4 N0-2 M0 squamous cell carcinoma of the oropharynx, hypopharynx or larynx are eligible. Exclusion criteria are recurrent disease, oncologic surgery to the head and neck area, concomitant chemotherapy or epidermal growth factor receptor inhibitors. In total, 300 patients will be randomized in a 2:1 ratio to a treatment arm with or without de-escalation of the elective radiation dose and introduction of an intermediate dose-level for selected lymph nodes. Radiation therapy planning FDG-PET/CT-scans will be acquired to guide risk assessment of borderline-sized cervical nodes that can be treated with the intermediate dose level. Treatment will be given with intensity-modulated radiation therapy or volumetric arc therapy with simultaneous-integrated boost using an accelerated fractionation schedule, 33 fractions in 5 weeks. The primary endpoint is 'normalcy of diet' at 1 year after treatment (toxicity). The secondary endpoint is the actuarial rate of recurrence in electively irradiated lymph nodes at 2 years after treatment (safety). DISCUSSION The objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and the introduction of an intermediate dose-level for borderline sized lymph nodes in the treatment of head and neck cancer will result in less radiation sequelae and improved quality of life after treatment without compromising the recurrence rate in the electively treated neck. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02442375 .
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Progression-free survival of early interim PET-positive patients with advanced stage Hodgkin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab (HD18): an open-label, international, randomised phase 3 study by the German Hodgkin Study Group.
Borchmann, P, Haverkamp, H, Lohri, A, Mey, U, Kreissl, S, Greil, R, Markova, J, Feuring-Buske, M, Meissner, J, Dührsen, U, et al
The Lancet. Oncology. 2017;(4):454-463
Abstract
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 (BEACOPPescalated) 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 BEACOPPescalated and centrally assessed by an expert panel. Patients with a positive PET after 2 cycles of BEACOPPescalated chemotherapy (PET-2) were randomly assigned (1:1) to receive six additional courses of either BEACOPPescalated (BEACOPPescalated group) or BEACOPPescalated plus rituximab (R-BEACOPPescalated group). PET-2 was assessed using a 5-point scale with 18FDG uptake higher than the mediastinal blood pool (corresponding to Deauville scale 3) defined as positive. BEACOPPescalated was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg), the first administration starting 24 h before starting the fourth cycle of BEACOPPescalated (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 BEACOPPescalated group (n=220) or the R-BEACOPPescalated 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 BEACOPPescalated group and 93·0% (89·4-96·6) for those in the R-BEACOPPescalated 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 BEACOPPescalated group vs 211 [96%] of 220 patients in the R-BEACOPPescalated 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 BEACOPPescalated group and ten (5%) of 220 in the R-BEACOPPescalated group died; fatal treatment-related toxic effects occurred in one (<1%) patient in the BEACOPPescalated group and three (1%) in the R-BEACOPPescalated group, all of them due to infection. INTERPRETATION The addition of rituximab to BEACOPPescalated 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.