Susanne Klutmann

Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial

BACKGROUND The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkins lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy. METHODS In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkins lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041. FINDINGS Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy. INTERPRETATION Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkins lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting. FUNDING Deutsche Krebshilfe and the Swiss Federal Government.

Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma

In the HD15 trial of the German Hodgkin Study Group, the negative predictive value (NPV) of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose in advanced-stage Hodgkin lymphoma (HL) was evaluated. A total of 817 patients were enrolled and randomly assigned to receive BEACOPP-based chemotherapy. After completion of chemotherapy, residual disease measuring more than or equal to 2.5 cm in diameter was assessed by PET in 311 patients. The NPV of PET was defined as the proportion of PET(-) patients without progression, relapse, or irradiation within 12 months after PET review panel. The progression-free survival was 96% for PET(-) patients (95% confidence interval [CI], 94%-99%) and 86% for PET(+) patients (95% CI, 78%-95%, P = .011). The NPV for PET in this analysis was 94% (95% CI, 91%-97%). Thus, consolidation radiotherapy can be omitted in PET(-) patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. The impact of this finding on the overall survival at 5 years must be awaited. Until then, response adapted therapy guided by PET for HL patients seems to be a promising approach that should be further evaluated in clinical trials. This trial is registered at http://isrctn.org study as #ISRCTN32443041.

Feasibility of 18F-Sodium Fluoride PET/CT for Imaging of Atherosclerotic Plaque

The aim of this study was to examine the prevalence, distribution, and topographic relationship of vascular 18F-sodium fluoride uptake and arterial calcification in major arteries. Methods: Image data obtained from 75 patients undergoing whole-body 18F-sodium fluoride PET/CT were evaluated retrospectively. Arterial radiotracer uptake and calcification were analyzed qualitatively and semiquantitatively. Results: 18F-sodium fluoride uptake was observed at 254 sites in 57 (76%) of the 75 study patients, and calcification was observed at 1,930 sites in 63 (84%) of the patients. Colocalization of radiotracer accumulation and calcification could be observed in 223 areas of uptake (88%). However, only 12% of all arterial calcification sites showed increased radiotracer uptake. Conclusion: Our data indicate the feasibility of 18F-sodium fluoride PET/CT for the imaging of mineral deposition in arterial wall alterations. 18F-sodium fluoride PET/CT may provide relevant information about the morphologic and functional properties of calcified plaque.

Correlation of Inflammation Assessed by 18F-FDG PET, Active Mineral Deposition Assessed by 18F-Fluoride PET, and Vascular Calcification in Atherosclerotic Plaque: A Dual-Tracer PET/CT Study

Formation and progression of atherosclerotic plaque is a dynamic and complex process involving various pathophysiologic steps including inflammation and calcification. The purpose of this study was to compare macrophage activity as determined by 18F-FDG PET and ongoing mineral deposition as measured by 18F-sodium fluoride PET in atherosclerotic plaque and to correlate these findings with calcified plaque burden as assessed by CT. Methods: Forty-five patients were examined by whole-body 18F-FDG PET, 18F-sodium fluoride PET, and CT. Tracer uptake in various arterial segments was analyzed both qualitatively and semiquantitatively by measuring the blood-pool–corrected standardized uptake value (target-to-background ratio [TBR]). The pattern of tracer uptake in atherosclerotic lesions was compared after color-coded multistudy image fusion of PET and CT studies. The Fisher exact test and the Spearman correlation coefficient rs were used for statistical analysis of image-based results and cardiovascular risk factors. Intra- and interrater reproducibility were evaluated using the Cohen κ. Results: 18F-sodium fluoride uptake was observed at 105 sites in 27 (60%) of the 45 study patients, and mean TBR was 2.3 ± 0.7. 18F-FDG uptake was seen at 124 sites in 34 (75.6%) patients, and mean TBR was 1.5 ± 0.3. Calcified atherosclerotic lesions were observed at 503 sites in 34 (75.6%) patients. Eighty-one (77.1%) of the 105 lesions with marked 18F-sodium fluoride uptake and only 18 (14.5%) of the 124 lesions with 18F-FDG accumulation were colocalized with arterial calcification. Coincident uptake of both 18F-sodium fluoride and 18F-FDG was observed in only 14 (6.5%) of the 215 arterial lesions with radiotracer accumulation. Conclusion: PET/CT with 18F-FDG and 18F-sodium fluoride may allow evaluation of distinct pathophysiologic processes in atherosclerotic lesions and might provide information on the complex interactions involved in formation and progression of atherosclerotic plaque.

In Vivo Imaging of Mineral Deposition in Carotid Plaque Using 18F-Sodium Fluoride PET/CT: Correlation with Atherogenic Risk Factors

The purpose of this study was to correlate 18F-sodium fluoride accumulation in the common carotid arteries of neurologically asymptomatic patients with cardiovascular risk factors and carotid calcified plaque burden. Methods: Two hundred sixty-nine oncologic patients were examined by 18F-sodium fluoride PET/CT. Tracer accumulation in the common carotid arteries was analyzed both qualitatively and semiquantitatively by measuring the blood-pool–corrected standardized uptake value (target-to-background ratio) and comparing it with cardiovascular risk factors and calcified plaque burden. Results: 18F-sodium fluoride uptake was observed at 141 sites in 94 (34.9%) patients. Radiotracer accumulation was colocalized with calcification in all atherosclerotic lesions. 18F-sodium fluoride uptake was significantly associated with age (P < 0.0001), male sex (P < 0.0001), hypertension (P < 0.002), and hypercholesterolemia (P < 0.05). The presence of calcified plaque correlated significantly with these risk factors but also with diabetes (P < 0.0001), history of smoking (P = 0.03), and prior cardiovascular events (P < 0.01). There was a highly significant correlation between the presence of 18F-sodium fluoride uptake and number of present cardiovascular risk factors (r = 0.30, P < 0.0001). Conclusion: Carotid 18F-sodium fluoride uptake is a surrogate measure of calcifying carotid plaque, correlates with cardiovascular risk factors, and is more frequent in patients with a high-risk profile for atherothrombotic events but demonstrates a weaker correlation with risk factors than does calcified plaque burden. This study provides a rationale to conduct further prospective studies to determine whether 18F-sodium fluoride uptake can predict vascular events, or if it may be used to monitor pharmacologic therapy.

Salivary gland protection by amifostine in high-dose radioiodine treatment: results of a double-blind placebo-controlled study.

PURPOSE Salivary gland impairment is a well-recognized side effect following high-dose radioiodine treatment (HD-RIT). Since differentiated thyroid cancer has a good prognosis, reduction of long-term side effects is important. Therefore, the effect of amifostine was studied in HD-RIT. PATIENTS AND METHODS Parenchymal function was assessed by quantitative salivary gland scintigraphy performed prospectively in 50 patients with differentiated thyroid cancer before and 3 months after HD-RIT with either 3 GBq iodine ((131)I) (n=21) or 6 GBq (131)I (n=29) in a double-blind, placebo-controlled study. Twenty-five patients were treated with 500 mg/m2 amifostine intravenously before HD-RIT and 25 patients served as controls, who received physiologic saline solution. Xerostomia was graded according to World Health Organization (WHO) criteria. RESULTS Before HD-RIT in 25 control patients, uptake of technetium-99m (99mTc)-pertechnetate was 0.45%+/-0.16% and 0.42%+/-0.16% in parotid and submandibular glands, respectively. Three months after HD-RIT, parenchymal function was significantly (P < .001) reduced by 40.2%+/-14.1% and 39.9%+/-15.3% in parotid and submandibular glands, respectively. Nine control patients developed grade I and two grade II xerostomia. In 25 amifostine-treated patients, uptake of 99mTc-pertechnetate was 0.46%+/-0.16% and 0.43%+/-0.17% in parotid and submandibular glands, respectively. Three months after HD-RIT, parenchymal function of salivary glands was not significantly altered (P=.691) and xerostomia did not occur in any of these patients. CONCLUSION Parenchymal damage in salivary glands caused by HD-RIT can significantly be reduced by amifostine, which may improve the quality of life of patients with differentiated thyroid cancer.

Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts

The hormone calcitonin (CT) is primarily known for its pharmacologic action as an inhibitor of bone resorption, yet CT-deficient mice display increased bone formation. These findings raised the question about the underlying cellular and molecular mechanism of CT action. Here we show that either ubiquitous or osteoclast-specific inactivation of the murine CT receptor (CTR) causes increased bone formation. CT negatively regulates the osteoclast expression of Spns2 gene, which encodes a transporter for the signalling lipid sphingosine 1-phosphate (S1P). CTR-deficient mice show increased S1P levels, and their skeletal phenotype is normalized by deletion of the S1P receptor S1P3. Finally, pharmacologic treatment with the nonselective S1P receptor agonist FTY720 causes increased bone formation in wild-type, but not in S1P3-deficient mice. This study redefines the role of CT in skeletal biology, confirms that S1P acts as an osteoanabolic molecule in vivo and provides evidence for a pharmacologically exploitable crosstalk between osteoclasts and osteoblasts.

Impact of DaTscan SPECT imaging on clinical management, diagnosis, confidence of diagnosis, quality of life, health resource use and safety in patients with clinically uncertain parkinsonian syndromes: a prospective 1-year follow-up of an open-label controlled study

Background This study assessed the impact of DaTscan on clinical management, diagnosis, confidence of diagnosis (CoD), quality of life (QoL), health resource use (HRU) and safety during a 1-year follow-up in patients with clinically uncertain parkinsonian syndromes (CUPS). Methods A total of 19 university hospital centres in Europe and the USA participated in this open-label, single-dose, prospective, clinical trial in patients with CUPS who were randomised to a DaTscan imaging group or to a no-imaging (control) group. The proportion of patients with changes in clinical management, diagnosis, CoD, QoL and HRU from baseline through 1 year post-DaTscan was compared between groups. Results There were 273 patients randomised (135 DaTscan, 138 control). Significantly more patients in the DaTscan imaging group had at least one change in their actual clinical management after 12 weeks (p=0.002) and after 1 year (p<0.001) compared with patients in the control group. In addition, significantly more DaTscan patients had changes in diagnosis and an increased CoD at 4 weeks, 12 weeks and 1 year (all p<0.001) compared with control patients. No significant differences in total score for QoL or HRU were observed between groups during the 1-year follow-up period. DaTscan was safe and well tolerated. One patient in the imaging group had an adverse event (headache) with suspected relationship to DaTscan post-administration. Conclusions DaTscan had a significant impact on clinical management, diagnosis and CoD in patients with CUPS. DaTscan is safe and well tolerated, and is a useful adjunct to differentiate a diagnosis of CUPS. Trial registration number http://ClinicalTrials.gov Identifier: NCT00382967.

Salivary gland protection by amifostine in high-dose radioiodine therapy of differentiated thyroid cancer

BackgroundSalivary gland impairment following high-dose radioiodine treatment is a well-recognized side effect, in general caused by free radicals. Therefore, it seemed promising to evaluate the radioprotective effect of the radical scavenger amifostine in patients receiving high-dose radioiodine therapy.Patients and MethodQuantitative salivary gland scintigraphy using 100 to 120 MBq Tc-99m-pertechnetate was performed in 17 patients with differentiated thyroid cancer prior to and 3 months after radioiodine treatment with 6 GBq 1–131. Eight patients were treated with 500 mg/m2 amifostine prior to high-dose radioiodine treatment and compared retrospectiveley with 9 control patients. Xerostomia was graded according to WHO criteria.ResultsIn 9 control patients high-dose radioiodine treatment significantly (p < 0.01) reduced Tc-99m-pertechnetate uptake by 35.4 ±22.0% and 31.7 ±21.1% in parotid and submandibular glands, respectively. Of these 9 patients, 3 exhibited xerostomia Grade I (WHO). In contrast, in 8 amifostine-treated patients, there was no significant (p = 0.878) decrease in parenchymal function following high-dose radioiodine treatment, and xerostomia did not occur in any of them.ConclusionParenchymal damage in salivary glands induced by high-dose radioiodine treatment can be reduced significantly by amifostine. This may help to increase patients’ quality of life in differentiated thyroid cancer.ZusammenfassungHintergrundEine SchÄdigung der Speicheldrüsen mit konsekutiver Xerostomie ist eine bekannte, durch freie Radikale verursachte Nebenwirkung der hochdosierten Radiojodtherapie bei Patienten mit differenziertem Schilddrüsenkarzinom. Daher wurde der Effekt des RadikalfÄngers Amifostin nach hochdosierter Radiojodtherapie geprüft.Patienten und MethodeIm Rahmen eines Heilversuchs wurde eine limitierte Anzahl von Patienten untersucht. Vor und drei Monate nach Gabe von 6 GBq 1–131 wurde eine quantitative Speicheldrüsenszintigraphie mit 100 bis 120 MBq Tc-99m-Pertechnetat an 17 Patienten mit differenzierten Schilddrüsenkarzinomen durchgeführt. Acht Patienten erhielten vor Radiojodtherapie 500 mg/m2 Amifostin und wurden mit einer historischen Kontrollgruppe aus neun Patienten verglichen. Eine Xerostomie wurde nach WHO-Kriterien beurteilt.ErgebnisseDie Patienten der Kontrollgruppe wiesen sowohl für die Glandulae parotides als auch für die Glandulae submandibulares eine signifikante Verminderung der Tc-99m-Pertechnetat-Aufnahme um 35,4 ±22,0% bzw. 31,7 +21, 1% (Abbildungen 1 und 2, Tabellen 1 und 2) als Zeichen einer ParenchymschÄdigung auf. Bei drei dieser neun Patienten fand sich eine Xerostomie Grad I (WHO). Im Gegensatz dazu konnte bei den mit Amifostin behandelten Patienten keine signifikante Verminderung der Parenchymfunktion festgestellt werden (p = 0,878). Dementsprechend wies keiner dieser Patienten eine Xerostomie auf.SchluΒfolgerungBei Patienten mit differenziertem Schilddrüsenkarzinom kann die durch hochdosierte Radiojodtherapie regelhaft verursachte ParenchymschÄdigung der Speicheldrüsen signifikant vermindert werden. Dies könnte die LebensqualitÄt dieser Patienten wesentlich verbessern.

18F-FDG PET/CT for detection and localization of residual or recurrent disease in patients with multiple myeloma after stem cell transplantation

PurposeThe aim of the study was to determine the diagnostic performance of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT for the detection and localization of residual or recurrent disease in patients with multiple myeloma (MM) after stem cell transplantation.MethodsA total of 197 whole-body 18F-FDG PET/CT scans were performed in 99 patients with MM at different time points in the course of disease after autologous or allogeneic stem cell transplantation. Post-transplant PET/CT scans and clinical remission status as determined by the clinical gold standard (Uniform Response Criteria) were analysed and compared.ResultsA total of 576 focal osseous and extramedullary lesions were detected in 79 scans. Additional diffuse bone marrow involvement was detected in 17 patients. 18F-FDG PET/CT had a sensitivity of 54.6%, a specificity of 82.1%, a positive predictive value of 82.3%, a negative predictive value of 54.2% and an overall accuracy of 65.5%. The sensitivity of 18F-FDG PET/CT was shown to depend on the disease category according to the Uniform Response Criteria for myeloma.ConclusionIn patients with MM in the post-transplant setting, 18F-FDG PET/CT may (1) contribute to the detection and localization of disease, (2) provide information about the extent of distinct myeloma manifestations and the total disease burden and (3) add information about the metabolic activity of disease, but (4) has substantially lower sensitivity for this purpose compared to the pretreatment setting.