Georg Kuhnert

Comparison of [18F]DCFPyL and [68Ga]Ga-PSMA-HBED-CC for PSMA-PET Imaging in Patients with Relapsed Prostate Cancer

PurposeGallium-68 (Ga-68)-labeled tracers for imaging expression of the prostate-specific membrane antigen (PSMA) such as the [68Ga]Ga-PSMA-HBED-CC have already demonstrated high potential for the detection of recurrent prostate cancer. However, compared to Ga-68, a labeling with fluorine-18 (F-18) would offer advantages with respect to availability, production amount, and image resolution. [18F]DCFPyL is a promising F-18-labeled candidate for PSMA-positron emission tomography (PET) imaging that has been recently introduced. In the current study, we aimed to compare [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL for clinical use in biochemically relapsed prostate cancer.ProceduresIn 14 selected patients with PSA relapse of prostate cancer, [18F]DCFPyL PET/X-ray computed tomography (CT) was performed in addition to [68Ga]Ga-PSMA-HBED-CC PET/CT. A systematic comparison was carried out between results obtained with both tracers with regard to the number of detected PSMA-positive lesions, the standardized uptake value (SUV)max and the lesion to background ratios.ResultsAll suspicious lesions identified by [68Ga]Ga-PSMA-HBED-CC were also detected with [18F]DCFPyL. In three patients, additional lesions were observed using [18F]DCFPyL PET/CT. The mean SUVmax in the concordant [18F]DCFPyL PSMA-positive lesions was significantly higher as compared to [68Ga]Ga-PSMA-HBED-CC (14.5 vs. 12.2, p = 0.028, n = 15). The mean tumor to background ratios (n = 15) were significantly higher for [18F]DCFPyL compared to [68Ga]Ga-PSMA-HBED-CC using kidney, spleen, or parotid as reference organs (p = 0.006, p = 0.002, p = 0.008), but no significant differences were found using the liver (p = 0.167) or the mediastinum (p = 0.363) as reference organs.Conclusion[18F]DCFPyL PET/CT provided a high image quality and visualized small prostate lesions with excellent sensitivity. [18F]DCFPyL represents a highly promising alternative to [68Ga]Ga-PSMA-HBED-CC for PSMA-PET/CT imaging in relapsed prostate cancer.

Assessment of Tumor Size Reduction Improves Outcome Prediction of Positron Emission Tomography/Computed Tomography After Chemotherapy in Advanced-Stage Hodgkin Lymphoma

PURPOSE Positron emission tomography (PET) after chemotherapy can guide consolidating radiotherapy in advanced-stage Hodgkin lymphoma (HL). This analysis aims to improve outcome prediction by integrating additional criteria derived by computed tomography (CT). PATIENTS AND METHODS The analysis set consisted of 739 patients with residues≥2.5 cm after chemotherapy from a total of 2,126 patients treated in the HD15 trial (HD15 for advanced stage Hodgkins disease: Quality assurance protocol for reduction of toxicity and the prognostic relevance of fluorodeoxyglucose-positron-emission tomography [FDG-PET] in the first-line treatment of advanced-stage Hodgkins disease) performed by the German Hodgkin Study Group. A central panel performed image analysis and interpretation of CT scans before and after chemotherapy as well as PET scans after chemotherapy. Prognosis was evaluated by using progression-free survival (PFS); groups were compared with the log-rank test. Potential prognostic factors were investigated by using receiver operating characteristic analysis and logistic regression. RESULTS In all, 548 (74%) of 739 patients had PET-negative residues after chemotherapy; these patients did not receive additional radiotherapy and showed a 4-year PFS of 91.5%. The 191 PET-positive patients (26%) receiving additional radiotherapy had a 4-year PFS of 86.1% (P=.022). CT alone did not allow further separation of patients in partial remission by risk of recurrence (P=.9). In the subgroup of the 54 PET-positive patients with a relative reduction of less than 40%, the risk of progression or relapse within the first year was 23.1% compared with 5.3% for patients with a larger reduction (difference, 17.9%; 95% CI, 5.8% to 30%). CONCLUSION Patients with HL who have PET-positive residual disease after chemotherapy and poor tumor shrinkage are at high risk of progression or relapse.

Brentuximab vedotin (SGN-35) in patients with transplant-naive relapsed/refractory Hodgkin lymphoma

Abstract Only limited data are available on the role of brentuximab vedotin (SGN-35) in transplant-naive relapsed or refractory patients with Hodgkin lymphoma (HL). We thus retrospectively analyzed 14 patients with primary refractory or relapsed HL who were treated with brentuximab vedotin as single agent in a named patient program, who had not received prior high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) due to refractory disease (n = 9), comorbidity (n = 4) and unknown reasons (n = 1). Brentuximab vedotin resulted in an overall response rate of 71% (10/14) with five complete responses (CRs). Five of those patients with refractory disease and four patients with relevant comorbidity responded. Consolidating ASCT (n = 4) or allogeneic SCT (n = 1) was performed in five patients. Median progression-free survival (PFS) was 9 months and the median overall survival (OS) was not reached. These data indicate the therapeutic efficacy of brentuximab vedotin in chemotherapy-refractory transplant-naive patients with HL.

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

BACKGROUND Advanced stage Hodgkins 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 Hodgkins 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 Hodgkins 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 Hodgkins 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 Hodgkins 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 Hodgkins lymphoma. FUNDING Deutsche Krebshilfe; Swiss State Secretariat for Education, Research and Innovation (SERI); and Roche Pharma.

PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma (HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group

BACKGROUND The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkins lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. METHODS In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkins lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1:1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 × eBEACOPP in total) or eBEACOPP with rituximab (8 × R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 × eBEACOPP) or experimental treatment with two additional cycles (4 × eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 × eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 × eBEACOPP and patients with negative PET-2 were randomly assigned to 6 × eBEACOPP (standard) or 4 × eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs ≥45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab was given intravenously at a dose of 375 mg/m2 (maximum total dose 700 mg). The primary objectives were to show superiority of the experimental treatment in the PET-2-positive cohort, and to show non-inferiority of the experimental treatment in the PET-2-negative cohort in terms of the primary endpoint, progression-free survival. We defined non-inferiority as an absolute difference of 6% in the 5-year progression-free survival estimates. Primary analyses in the PET-2-negative cohort were per protocol; all other analyses were by intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00515554. FINDINGS Between May 14, 2008, and July 18, 2014, we recruited 2101 patients, of whom 137 were found ineligible before randomisation and a further 19 were found ineligible after randomisation. Among 434 randomised patients (217 per arm) with positive PET-2, 5-year progression-free survival was 89·7% (95% CI 85·4-94·0) with eBEACOPP and 88·1% (83·5-92·7) with R-eBEACOPP (log-rank p=0·46). Patients with negative PET-2 randomly assigned to either 8 × eBEACOPP or 6 × eBEACOPP (n=504) or 4 × eBEACOPP (n=501) had 5-year progression-free survival of 90·8% (95% CI 87·9-93·7) and 92·2% (89·4-95·0), respectively (difference 1·4%, 95% CI -2·7 to 5·4). 4 × eBEACOPP was associated with fewer severe infections (40 [8%] of 498 vs 75 [15%] of 502) and organ toxicities (38 [8%] of 498 vs 91 [18%] of 502) than were 8 × eBEACOPP or 6 × eBEACOPP in PET-2-negative patients. Ten treatment-related deaths occurred: four in the PET-2-positive cohort (one [<1%] in the 8 × eBEACOPP group, three [1%] in the 8 × R-eBEACOPP group) and six in the PET-2-negative group (six [1%] in the 8 × eBEACOPP or 6 × eBEACOPP group). INTERPRETATION The favourable outcome of patients treated with eBEACOPP could not be improved by adding rituximab after positive PET-2. PET-2 negativity allows reduction to only four cycles of eBEACOPP without loss of tumour control. PET-2-guided eBEACOPP provides outstanding efficacy for all patients and increases overall survival by reducing treatment-related risks for patients with negative PET-2. We recommend this PET-2-guided treatment strategy for patients with advanced-stage Hodgkins lymphoma. FUNDING Deutsche Krebshilfe, Swiss State Secretariat for Education and Research, and Roche Pharma AG.

In vivo Patterns of Tau Pathology, Amyloid-β Burden, and Neuronal Dysfunction in Clinical Variants of Alzheimer’s Disease

The clinical heterogeneity of Alzheimers disease is not reflected in the rather diffuse cortical deposition of amyloid-β. We assessed the relationship between clinical symptoms, in vivo tau pathology, amyloid distribution, and hypometabolism in variants of Alzheimers disease using novel multimodal PET imaging techniques. Tau pathology was primarily observed in brain regions related to clinical symptoms and overlapped with areas of hypometabolism. In contrast, amyloid-β deposition was diffusely distributed over the entire cortex. Tau PET imaging may thus serve as a valuable biomarker for the localization of neuronal injury in vivo and may help to validate atypical subtypes of Alzheimers disease.

18-Fluorodeoxyglucose positron emission tomography/computed tomography for assessment of response to brentuximab vedotin treatment in relapsed and refractory Hodgkin lymphoma.

Abstract Brentuximab vedotin has emerged as a possible treatment option in patients suffering from relapsed and refractory Hodgkin lymphoma (HL). We investigated the role of 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for monitoring treatment response to brentuximab vedotin in patients with relapsed and refractory HL. Twelve consecutive, heavily pretreated patients with relapsed and refractory HL treated with brentuximab vedotin were available for analysis. FDG-PET/CT studies were performed early during treatment after a median of 3 cycles (range, 2–5 cycles), and were analyzed visually using a 5-point scale (5PS) and quantitatively using the maximum standardized uptake value (SUVmax) and the three-dimensional (3D) isocontour at 50% of the maximum pixel value (SUV50) in the hottest single lesion. The median follow-up in our study cohort was 16 months (range, 5–30 months). The median progression-free survival (PFS) was 12.5 months and PFS at 12 months was 58%. Patients treated with brentuximab vedotin and negative interim FDG-PET/CT assessed by visual or quantitative analysis demonstrated a significantly prolonged PFS compared to patients with positive interim FDG-PET/CT. The 1-year PFS was 100% in patients with negative interim FDG-PET/CT assessed by visual analysis, whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 38% (p = 0.033). The 1-year PFS was 75% in patients with negative interim FDG-PET/CT assessed by quantitative analysis using the SUV50, whereas patients with positive interim FDG-PET/CT had a worse outcome with a 1-year PFS of 25% (p = 0.017) Interim FDG-PET/CT might be a suitable diagnostic approach to predict response to brentuximab vedotin in relapsed and refractory HL.

Incorporation of brentuximab vedotin into first-line treatment of advanced classical Hodgkin's lymphoma: final analysis of a phase 2 randomised trial by the German Hodgkin Study Group

BACKGROUND A high proportion of patients with relapsed classical Hodgkins lymphoma achieve a response with the antibody-drug conjugate brentuximab vedotin, and the drug is well tolerated. We modified the escalated BEACOPP regimen (eBEACOPP; bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and implemented brentuximab vedotin with the aim to reduce toxic effects while maintaining the protocols efficacy. METHODS We did an open-label, multicentre, randomised phase 2 study at 20 study sites in Germany. Adult patients (aged 18-60 years) with newly diagnosed, advanced, classical Hodgkins lymphoma were randomly assigned (1:1) to treatment with six cycles of either BrECAPP (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 200 mg/m2 on days 2-4, doxorubicin 35 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, procarbazine 100 mg/m2 on days 2-8, and prednisone 40 mg/m2 on days 2-15) or BrECADD (brentuximab vedotin 1·8 mg/kg on day 1, etoposide 150 mg/m2 on days 2-4, doxorubicin 40 mg/m2 on day 2, cyclophosphamide 1250 mg/m2 on day 2, dacarbazine 250 mg/m2 on days 3-4, and dexamethasone 40 mg on days 2-5). Randomisation was done centrally by stratified minimisation, with study site and sex as stratification factors. The co-primary endpoints were complete response to chemotherapy and complete remission at the end of treatment, which were assessed by intention to treat. Patients who were found not to meet inclusion criteria after randomisation or without restaging data after two cycles of study treatment were excluded from the primary endpoint analysis. All patients who started study treatment were assessable for safety. This report presents the final analysis at a median follow-up of 17 months (IQR 13·2-21·5). The preplanned 2-year follow-up analysis is yet to be reported. This trial is registered with ClinicalTrials.gov, number NCT01569204. FINDINGS Between Oct 26, 2012, and May 15, 2014, 104 patients were enrolled to the study (52 were assigned to each study arm). Two patients dropped out before the start of study treatment because of acute infection (n=1) and withdrawal of consent (n=1) and one patient was excluded because of intermediate-stage disease (all were assigned BrECAPP). 42 (86%, 95% CI 73-94) of 49 patients assigned BrECAPP achieved a complete response after chemotherapy and 46 (94%, 95% CI 83-99) had complete remission as their final treatment outcome. In the BrECADD group, 46 (88%, 95% CI 77-96) of 52 patients achieved both a complete response after chemotherapy and complete remission as their final treatment outcome. 58 serious adverse events were reported, 32 events in 21 of 50 patients who received BrECAPP and 26 events in 18 of 52 patients who received BrECADD. The most common grade 3-4 toxic effects were haematological adverse events (91 [89%] of 102 patients). Grade 3-4 organ toxic effects were reported in seven (17%) of 42 patients assigned BrECAPP and two (4%) of 46 allocated BrECADD. 16 (32%) of 50 patients assigned BrECAPP and 18 (35%) of 52 allocated BrECADD had grade 1-2 peripheral neuropathy, and one (2%) patient assigned BrECAPP developed grade 3 peripheral neuropathy; all but one case (allocated BrECAPP) resolved. No deaths were reported during the follow-up period. INTERPRETATION Both eBEACOPP variants met the co-primary efficacy endpoints. Particularly, the BrECADD regimen was associated with a more favourable toxicity profile and was, therefore, selected to challenge standard eBEACOPP for the treatment of advanced classical Hodgkins lymphoma in the phase 3 HD21 study by the German Hodgkin Study Group (NCT02661503), which aims to further reduce treatment-related morbidity. FUNDING Takeda Pharmaceuticals.

Relapse Analysis of Irradiated Patients Within the HD15 Trial of the German Hodgkin Study Group

PURPOSE To determine, in the setting of advanced-stage of Hodgkin lymphoma (HL), whether relapses occur in the irradiated planning target volume and whether the definition of local radiation therapy (RT) used by the German Hodgkin Study Group (GHSG) is adequate, because there is no harmonization of field and volume definitions among the large cooperative groups in the treatment of advanced-stage HL. METHODS AND MATERIALS All patients with residual disease of ≥ 2.5 cm after multiagent chemotherapy (CTX) were evaluated using additional positron emission tomography (PET), and those with a PET-positive result were irradiated with 30 Gy to the site of residual disease. We re-evaluated all sites of disease before and after CTX, as well as the PET-positive residual tumor that was treated in all relapsed patients. Documentation of radiation therapy (RT), treatment planning procedures, and portal images were carefully analyzed and compared with the centrally recommended RT prescription. The irradiated sites were compared with sites of relapse using follow-up computed tomography scans. RESULTS A total of 2126 patients were enrolled, and 225 patients (11%) received RT. Radiation therapy documents of 152 irradiated patients (68%) were analyzed, with 28 irradiated patients (11%) relapsing subsequently. Eleven patients (39%) had an in-field relapse, 7 patients (25%) relapsed outside the irradiated volume, and an additional 10 patients (36%) showed mixed in- and out-field relapses. Of 123 patients, 20 (16%) with adequately performed RT relapsed, compared with 7 of 29 patients (24%) with inadequate RT. CONCLUSIONS The frequency and pattern of relapses suggest that local RT to PET-positive residual disease is sufficient for patients in advanced-stage HL. Insufficient safety margins of local RT may contribute to in-field relapses.

Metabolic Tumour Volume for Response Prediction in Advanced-Stage Hodgkin Lymphoma

18F-FDG PET/CT for staging Hodgkin lymphoma may allow for accurate and reliable assessment of the metabolic tumor volume (MTV) as a baseline risk factor. Our aim was to analyze 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 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 4 different thresholding methods and performed receiver-operating-characteristic analysis to evaluate the potential for prediction of early response determined by PET after 2 cycles (PET-2) of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP). Logistic regression was used to evaluate its prognostic value concerning progression-free survival and overall survival. Results: All of the different MTV calculations 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 receiver-operating-characteristic curves point to any unique cutoffs; rather, a wide range of possible cutoffs was indicated. None of the MTV measurements was prognostic for progression-free survival (hazard ratio, 1.2–1.5; P = 0.15–0.52) or overall survival (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 2 cycles. However, value as a prognostic factor after a highly effective PET-2–adapted treatment strategy could not be observed.