Niklaus Schaefer

New Derivatives of Vitamin B12 Show Preferential Targeting of Tumors

Rapidly growing cells show an increased demand for nutrients and vitamins. The objective of our work is to exploit the supply route of vitamin B12 to deliver new derivatives of this vital vitamin to hyperproliferative cells. To date, radiolabeled ((57)Co and (111)In) vitamin B12 derivatives showed labeling of tumor tissue but also undesired high accumulation of radioactivity in normal tissue. By abolishing the interaction of a tailored vitamin B12 derivative to its transport protein transcobalamin II and therefore interrupting transcobalamin II receptor and megalin mediated uptake in normal tissue, preferential accumulation of a radiolabeled vitamin in cancer tissue could be accomplished. We identified transcobalamin I on tumors as a possible new receptor for this preferential accumulation of vitamin-mediated targeting. The low systemic distribution of radioactivity and the high tumor to blood ratio opens the possibility of a more successful clinical application of vitamin B12 for imaging or therapy.

Combined FDG-PET/CT in response evaluation of malignant pleural mesothelioma

PURPOSE Based on the complex growth pattern of MPM, conventional response evaluation in this cancer entity is challenging. Therefore, there is growing interest in therapy response evaluation with FDG-PET/CT. The aim of the study was to evaluate the value of several FDG-PET/CT-parameters in therapy response evaluation concerning prediction of survival at baseline and after three cycles of therapy. PATIENTS AND METHODS The study was performed in accordance with the regulations of the local ethics committee. Forty-one patients with proven MPM and treated with palliative pemetrexed and platinum-based chemotherapy were included. All patients were evaluated by FDG-PET/CT at baseline and after three cycles of chemotherapy. Responders and non-responders were evaluated based on modified RECIST- and EORTC-criteria. Additional PET-parameters (SUVmean, tumor lesion glycolysis (TLG) and tumor volume (PETvol)) were evaluated. Results were evaluated using the COX regression and the Kaplan-Meier method. RESULTS None of the baseline CT-measurements or the initial PET-parameters were predictive for survival. Based on CT, after three cycles of therapy 10 patients were categorized as responders, 30 were classified as stable disease and 1 had progressive disease. Based on PET-evaluation, 14 responders were identified, 23 patients with stable disease and 4 patients were progressive. CT-response after 3 cycles of chemotherapy was significantly related to overall survival (p=0.001). However, neither SUVmax-response (p=0.61) nor SUVmean-response (p=0.68) were related to survival. A decrease of TLG and PETvol, however, was found to be predictive (TLG: p=0.01; PETvol: p=0.002). CONCLUSION Response evaluation based on modified RECIST by CT as well as response evaluation by TLG and PETvol in FDG-PET, but not SUVmax-measurements are predictive for survival in MPM.

Hodgkin’s lymphoma in remission after first-line therapy: which patients need FDG–PET/CT for follow-up?

BACKGROUND The purpose of the study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET)/computed tomography (CT) during follow-up of patients with Hodgkins lymphoma. PATIENTS AND METHODS Patients in complete remission or an unconfirmed complete remission after first-line therapy who received FDG-PET/CT during their follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in case of recurrence. RESULTS Overall, 134 patients were analyzed. Forty-two (31.3%) patients had a recurrence. The positive predictive value of FDG-PET/CT was 0.98. Single-factor analysis identified morphological residual mass [P = 0.0005, hazard ratio (HR) 3.4, 95% confidence interval (CI) 1.7-6.6] and symptoms (P < 0.0001, HR 4.9, 95% CI 2.4-9.9) as significant risk factors for relapse. By multivariate analysis, morphological residual mass was the only significant risk factor for early follow-up (<24 months) (P = 0.0019, HR 7.6, 95% CI 2.1-27.3). Advanced stage (P = 0.0426, HR 3.6, 95% CI 1.1-12.3) and the presence of symptoms (P = 0.0009, HR = 14.6, 95% CI 3.0-69.7) were found to be significant risk factors for later follow-up (>24 months). CONCLUSIONS Asymptomatic patients without morphological residues and an early stage of disease do not need a routine FDG-PET/CT for follow-up. Asymptomatic patients with morphological residues should receive routine follow-up FDG-PET/CT for the first 24 months. Only patients with advanced initial stage do need a routine follow-up FDG-PET/CT beyond 24 months.

Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer.

The aim of this first-in-man study was to demonstrate the feasibility, safety, and tolerability, as well as provide dosimetric data and evaluate the imaging properties, of the bombesin analogue BAY 864367 for PET/CT in a small group of patients with primary and recurrent prostate cancer (PCa). Methods: Ten patients with biopsy-proven PCa (5 with primary PCa and 5 with prostate-specific antigen recurrence after radical prostatectomy) were prospectively selected for this exploratory clinical trial with BAY 864367, a new 18F-labeled bombesin analogue. PET scans were assessed at 6 time points, up to 110 min after intravenous administration of 302 ± 11 MBq of BAY 864367. Imaging results were compared with 18F-fluorocholine PET/CT scans. Dosimetry was calculated using the OLINDA/EXM software. Results: Three of 5 patients with primary disease showed positive tumor delineation in the prostate, and 2 of 5 patients with biochemical relapse showed a lesion suggestive of recurrence on the BAY 864367 scan. Tumor-to-background ratio averaged 12.9 ± 7.0. The ratio of malignant prostate tissue to normal prostate tissue was 4.4 ± 0.6 in 3 patients with tracer uptake in the primary PCa. Mean effective dose was 4.3 ± 0.3 mSv/patient (range, 3.7–4.9 mSv). Conclusion: BAY 864367, a novel 18F-labeled bombesin tracer, was successfully investigated in a first-in-man clinical trial of PCa and showed favorable dosimetric values. Additionally, the application was safe and well tolerated. The tracer delineated tumors in a subset of patients, demonstrating the potential of gastrin-releasing-peptide receptor imaging.

Risk-adapted FDG–PET/CT-based follow-up in patients with diffuse large B-cell lymphoma after first-line therapy

BACKGROUND The purpose of this study was to evaluate the impact of 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) during follow-up of patients with diffuse large B-cell lymphoma (DLBCL) being in complete remission or unconfirmed complete remission after first-line therapy. PATIENTS AND METHODS DLBCL patients receiving FDG-PET/CT during follow-up were analyzed retrospectively. Confirmatory biopsy was mandatory in cases of suspected disease recurrence. RESULTS Seventy-five patients were analyzed and 23 (30%) had disease recurrence. The positive predictive value (PPV) of FDG-PET/CT was 0.85. Patients >60 years [P = 0.036, hazard ratio (HR) = 3.82, 95% confidence interval (CI) 1.02-7.77] and patients with symptoms indicative of a relapse (P = 0.015; HR = 4.1; 95% CI 1.20-14.03) had a significantly higher risk for relapse. A risk score on the basis of signs of relapse, age >60 years, or a combination of these factors identified patients at high risk for recurrence (P = 0.041). CONCLUSIONS FDG-PET/CT detects recurrent DLBCL after first-line therapy with high PPV. However, it should not be used routinely and if only in selected high-risk patients to reduce radiation burden and costs. On the basis of our retrospective data, FDG-PET/CT during follow-up is indicated for patients <60 years with clinical signs of relapse and in patients >60 years with and without clinical signs of relapse.

Computed tomographic perfusion imaging for the prediction of response and survival to transarterial radioembolization of liver metastases.

PurposeThe purpose of this study was to evaluate prospectively, in patients with liver metastases, the ability of computed tomographic (CT) perfusion to predict the morphologic response and survival after transarterial radioembolization (TARE). MethodsThirty-eight patients (22 men; mean [SD] age, 63 [12] years) with otherwise therapy-refractory liver metastases underwent dynamic, contrast-enhanced CT perfusion within 1 hour before treatment planning catheter angiography, for calculation of the arterial perfusion (AP) of liver metastases, 20 days before TARE with Yttrium-90 microspheres. Treatment response was evaluated morphologically on follow-up imaging (mean, 114 days) on the basis of the Response Evaluation Criteria in Solid Tumors criteria (version 1.1). Pretreatment CT perfusion was compared between responders and nonresponders. One-year survival was calculated including all 38 patients using the Kaplan-Meier curves; the Cox proportional hazard model was used for calculating predictors of survival. ResultsFollow-up imaging was not available in 11 patients because of rapidly deteriorating health or death. From the remaining 27, a total of 9 patients (33%) were classified as responders and 18 patients (67%) were classified as nonresponders. A significant difference in AP was found on pretreatment CT perfusion between the responders and the nonresponders to the TARE (P < 0.001). Change in tumor size on the follow-up imaging correlated significantly and negatively with AP before the TARE (r = −0.60; P = 0.001). Receiver operating characteristics analysis of AP in relation to treatment response revealed an area under the curve of 0.969 (95% confidence interval, 0.911–1.000; P < 0.001). A cutoff AP of 16 mL per 100 mL/min was associated with a sensitivity of 100% (9/9) (95% CI, 70%–100%) and a specificity of 89% (16/18) (95% CI, 62%–96%) for predicting therapy response. A significantly higher 1-year survival after the TARE was found in the patients with a pretreatment AP of 16 mL per 100 mL/min or greater (P = 0.028), being a significant, independent predictor of survival (hazard ratio, 0.101; P = 0.015). ConclusionsArterial perfusion of liver metastases, as determined by pretreatment CT perfusion imaging, enables prediction of short-term morphologic response and 1-year survival to TARE.

Early Treatment Response Evaluation after Yttrium-90 Radioembolization of Liver Malignancy with CT Perfusion

PURPOSE To evaluate computed tomography (CT) perfusion for assessment of early treatment response after transarterial radioembolization of patients with liver malignancy. MATERIALS AND METHODS Dynamic contrast-enhanced CT liver perfusion was performed before and 4 weeks after transarterial radioembolization in 40 patients (25 men and 15 women; mean age, 64 y ± 11; range, 35-80 y) with liver metastases (n = 27) or hepatocellular carcinoma (HCC) (n = 13). Arterial perfusion (AP) of tumors derived from CT perfusion and tumor diameters were measured on CT perfusion before and after transarterial radioembolization. Success of transarterial radioembolization was evaluated on morphologic follow-up imaging (median follow-up time, 4 mo) based on Response Evaluation Criteria in Solid Tumors (Version 1.1). CT perfusion parameters before and after transarterial radioembolization for different response groups were compared. Kaplan-Meier curves were plotted to illustrate overall 1-year survival rates. RESULTS Liver metastases showed significant differences in AP before and after transarterial radioembolization in responders (P < .05) but not in nonresponders (P = .164). In HCC, AP values before and after transarterial radioembolization were not significantly different in responders and nonresponders (P = .180 and P = .052). Tumor diameters were not significantly different on CT perfusion before and after transarterial radioembolization in responders and nonresponders with liver metastases and HCC (P = .654, P = .968, P = .148, P = .164). In patients with significant decrease of AP in liver metastases after transarterial radioembolization, 1-year overall survival was significantly higher than in patients showing no reduction of AP. CONCLUSIONS CT perfusion showed early reduction of AP in liver metastases responding to transarterial radioembolization; tumor diameter remained unchanged early after treatment. No significant early treatment response to transarterial radioembolization was found in patients with HCC. In patients with liver metastases, a decrease of AP after transarterial radioembolization was associated with a higher 1-year overall survival rate.

Potential use of humanized antibodies in the treatment of breast cancer

With the growing knowledge of key cellular pathways in tumor induction and evolution, targeted therapies make up an increasing proportion of new drugs entering clinical testing. In the treatment of breast cancer, humanized antibodies have become a major option. The humanized monoclonal antibody trastuzumab (Herceptin®; Genentech, Inc., CA, USA) for HER2-overexpressing, metastatic breast cancer, represents a successful agent associated with impressive survival benefits when combined with chemotherapy. Based on impressive results, trastuzumab will become a standard in the adjuvant treatment of HER2-overexpressing breast cancer. The role of trastuzumab in the neoadjuvant setting is promising, but must be further evaluated in large prospective, randomized trials. However, there is still a large proportion of patients overexpressing HER2 that do not respond to trastuzumab. Regarding this patient cohort, the optimal combination of trastuzumab with other agents needs further evaluation. In breast cancer lacking HER2 amplification, the role of the new antibody pertuzumab remains to be defined. The role of antibodies interfering with angiogenesis, tumor stroma or glycoproteins is of a preliminary nature and warrants further investigation. Here, an overview of humanized antibodies in human breast cancer is provided, with emphasis on the recent advances and future prospects in treating malignant breast cancer.

Continued pemetrexed and platin-based chemotherapy in patients with malignant pleural mesothelioma (MPM): Value of 18F-FDG-PET/CT

PURPOSE To prospectively analyze different FDG-PET/CT-parameters (modified RECIST, SUVmax, TLG, PETvol) in patients with malignant pleural mesothelioma (MPM) under continued pemetrexed and platin based treatment. METHODS Patients with biopsy proven MPM undergoing treatment with pemetrexed and platin based treatment were prospectively included in the study. Integrated FDG-PET/CT imaging was performed within 2 weeks before therapy and after every three consecutive cycles of combined chemotherapy. All CT-images were evaluated according to the modified RECIST (modRECIST) criteria. All FDG-PET/CT images were analyzed using SUVmax (maximum Standard Uptake Value) according to the EORTC criteria, change in Total Lesion Glycolysis (TLG) and FDG volume (PETvol). Percent change in all parameters compared to the initial, pre-therapeutic and the previous FDG-PET/CT scan. ModRECIST, EORTC guidelines, increase or decrease in TLG and PETvol was correlated with overall survival (OS) using the Log Rank Test. RESULTS 41 patients with MPM were prospectively included in this study. The median OS of the study population is 439 days (111-1128). 41 patients had initial staging, 41 patients completed 3 cycles, 28 patients completed 6 cycles, 19 patients completed 9 cycles, 11 patients completed 12 cycles, 5 patients completed 15 cycles, 4 patients completed 18 cycles and 1 patient completed 21 cycles of chemotherapy. Chemotherapy was well tolerated up to 21 cycles. SUVmax showed a high variance over time for individual patients and change in SUVmax using EORTC guidelines did not predict OS at any time point. Ongoing morphological response in CT using modRECIST had highest correlation with OS and predicted survival up to the 15th cycle of continued permetrexed and platin based treatment. The correlations of response of the volume based PET parameters (TLG and PETvol) and OS are inferior to the morphological modRECIST parameter. CONCLUSION Permetrexed and platin based treatment in MPM patients can be given over a prolonged time with good tolerance. Therapy response should be assessed by modRECIST in CT but not with SUVmax in FDG-PET. Long term permetrexed and platin therapy should be considered in MPM patients with good tolerance of treatment and ongoing morphological response in CT.

Influence of Bowel Preparation Before 18F-FDG PET/CT on Physiologic 18F-FDG Activity in the Intestine

Our objective was to investigate the use of bowel preparation before 18F-FDG PET/CT to reduce intestinal 18F-FDG uptake. Methods: Sixty-five patients with abdominal neoplasias were assigned either to a bowel-preparation group (n = 26) or to a native group (n = 39). 18F-FDG activity was measured in the small intestine and the colon. Results: In the 26 patients with bowel preparation, average maximal standardized uptake value (SUVmax) was 3.5 in the small intestine and 4.4 in the colon. In the 39 patients without bowel preparation, average SUVmax was 2.6 in the small intestine and 2.7 in the colon. 18F-FDG activity impaired diagnosis in 6 patients (23%) in the bowel-preparation group and 11 patients (28%) in the native group (P = 0.5). SUVmax in the colon was significantly higher in the bowel-preparation group (P = 0.002), but SUVmax in the small intestine did not significantly differ between the 2 groups (P = 0.088). Conclusion: Bowel preparation increases 18F-FDG activity in the large intestine and is therefore not useful before PET/CT.