Daniela E. Oprea-Lager

Radiopharmaceuticals for Palliation of Bone Pain in Patients with Castration-resistant Prostate Cancer Metastatic to Bone: A Systematic Review

CONTEXT The majority of patients with castration-resistant prostate cancer develop bone metastatic disease. It is often challenging to optimally palliate malignant bone pain. In case of multifocal pain due to diffuse osteoblastic metastases, treatment with bone-seeking radiopharmaceuticals can be considered. OBJECTIVE This systematic review evaluates the efficacy of different bone-seeking radiopharmaceuticals for palliation of malignant bone pain from prostate cancer. EVIDENCE ACQUISITION The PubMed (Medline) and Embase databases were searched for publications on 89-strontium-chloride ((89)Sr), 153-samarium-EDTMP ((153)Sm), 186-rhenium-HEDP ((186)Re), 188-rhenium-HEDP ((188)Re), and 223-radium-chloride ((223)Ra). Randomised controlled trials and prospective cohort studies were included. Metastatic bone pain had to be registered as outcome measure for prostate cancer patients separately. EVIDENCE SYNTHESIS This review included 36 articles of which 13 randomised trials and 23 prospective studies. Of all trials, 10 studies used (89)Sr, 7 (153)Sm, 12 (186)Re, 2 (188)Re, and 2 (223)Ra; three reported on a combination of different radionuclides. Only a few trials contained a blinding procedure and several studies contained incomplete follow-up or lack of intention-to-treat analysis. It was not possible to calculate a pooled estimate of pain response to treatment with any of the radionuclides because different definitions of pain response were used. CONCLUSIONS Overall, pain response percentages greater than 50-60% were seen with each radionuclide. Haematological toxicity was reported in 26 of the 36 studies and more than half of these trials stated no grade 3/4 leukopenia or thrombocytopenia occurred. PATIENT SUMMARY In this report we reviewed the efficacy of bone-seeking radionuclides for treating bone pain from metastatic prostate cancer. Overall, treatment with bone-seeking radionuclides resulted in pain responses greater than 50-60%.

Dual-phase PET-CT to differentiate [18F]Fluoromethylcholine uptake in reactive and malignant lymph nodes in patients with prostate cancer.

Purpose To investigate whether time-trends of enhanced [18F]Fluoromethylcholine ([18F]FCH) in lymph nodes (LN) of prostate cancer (PCa) patients can help to discriminate reactive from malignant ones, and whether single time point standardized uptake value (SUV) measurements also suffice. Procedures 25 PCa patients with inguinal (presumed benign) and enlarged pelvic LN (presumed malignant) showing enhanced [18F]FCH uptake at dual-phase PET-CT were analyzed. Associations between LN status (benign versus malignant) and SUVmax and SUVmeanA50, determined at 2 min (early) and 30 min (late) post injection, were assessed. We considered two time-trends of [18F]FCH uptake: type A (SUV early > SUV late) and type B (SUV late ≥ SUV early). Histopathology and/or follow-up were used to confirm the assumption that LN with type A pattern are benign, and LN with type B pattern malignant. Results Analysis of 54 nodes showed that LN status, time-trends, and ‘late’ (30 min p.i.) SUVmax and SUVmeanA50 parameters were strongly associated (P<0.0001). SUVmax relative difference was the best LN status predictor. All but one inguinal LN showed a decreasing [18F]FCH uptake over time (pattern A), while 95% of the pelvic nodes presented a stable or increasing uptake (pattern B) type. Conclusions Time-trends of enhanced [18F]FCH uptake can help to characterize lymph nodes in prostate cancer patients. Single time-point SUV measurements, 30 min p.i., may be a reasonable alternative for predicting benign versus malignant status of lymph nodes, but this remains to be validated in non-enlarged pelvic lymph nodes.

Whole-body-MR imaging including DWIBS in the work-up of patients with head and neck squamous cell carcinoma: A feasibility study

OBJECTIVES To assess the feasibility of whole-body magnetic resonance imaging (WB-MRI) including diffusion-weighted whole-body imaging with background-body-signal-suppression (DWIBS) for the evaluation of distant malignancies in head and neck squamous cell carcinoma (HNSCC); and to compare WB-MRI findings with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) and chest-CT. METHODS Thirty-three patients with high risk for metastatic spread (26 males; range 48-79 years, mean age 63 ± 7.9 years (mean ± standard deviation) years) were prospectively included with a follow-up of six months. WB-MRI protocol included short-TI inversion recovery and T1-weighted sequences in the coronal plane and half-fourier acquisition single-shot turbo spin-echo T2 and contrast-enhanced-T1-weighted sequences in the axial plane. Axial DWIBS was reformatted in the coronal plane. Interobserver variability was assessed using weighted kappa and the proportion specific agreement (PA). RESULTS Two second primary tumors and one metastasis were detected on WB-MRI. WB-MRI yielded seven clinically indeterminate lesions which did not progress at follow-up. The metastasis and one second primary tumor were found when combining (18)F-FDG-PET/CT and chest-CT findings. Interobserver variability for WB-MRI was κ=0.91 with PA ranging from 0.82 to 1.00. For (18)F-FDG-PET/CT κ could not be calculated due to a constant variable in the table and PA ranged from 0.40 to 0.99. CONCLUSIONS Our WB-MRI protocol with DWIBS is feasible in the work-up of HNSCC patients for detection and characterization of distant pathology. WB-MRI can be complementary to (18)F-FDG-PET/CT, especially in the detection of non (18)F-FDG avid second primary tumors.

Repeatability of quantitative 18F-fluoromethylcholine PET/CT studies in prostate cancer

Repeatable quantification is essential when using 18F-fluoromethylcholine PET/CT to monitor treatment response in prostate cancer. It has been shown that SUV normalized to the area under the blood activity concentration curve (SUVAUC) provides a better correlation with full kinetic analysis than does standard SUV. However, the precision of SUVAUC is not known yet. The purpose of this study was to assess the repeatability of various semiquantitative 18F-fluoromethylcholine parameters in prostate cancer. Methods: Twelve patients (mean age ± SD, 64 ± 8 y) with metastasized prostate cancer underwent two sets of 18F-fluoromethylcholine PET/CT scans, on consecutive days. Each set consisted of a 30-min dynamic PET/CT scan of the chest after intravenous administration of 200 MBq of 18F-fluoromethylcholine, followed by a whole-body PET/CT scan at 40 min. The dynamic scan was used to derive the area under the blood activity concentration curve. Lesion uptake was derived from the whole-body scan using various types of volumes of interest: maximum, peak, and mean. Each of these parameters was normalized to injected activity per body weight, area under the blood activity concentration curve, and blood concentration itself at 40 min, resulting in several types of SUVs: SUV, SUVAUC, and SUVTBR. The test–retest repeatability of these metrics, as well as metabolic tumor volume (MTV) and total uptake of choline in the lesion, were studied. The level of agreement between test–retest data and reliability was assessed using Bland–Altman plots, repeatability coefficients, and intraclass correlation coefficients (ICCs). Results: A total of 67 choline-avid metastases were identified: 44 bone lesions and 23 lymph node lesions. In the case of SUVmax, the repeatability coefficients for SUV, SUVAUC, and SUVTBR were 26% (ICC, 0.95), 31% (ICC, 0.95), and 46% (ICC, 0.89), respectively. Similar values were obtained for SUVpeak and SUVmean. The repeatability of SUVAUC was comparable to that of SUVmax, SUVpeak, and SUVmean. Tissue type and tumor localization did not affect repeatability. An MTV of less than 4.2 cm3 had larger variability than larger volumes (repeatability coefficient, 45% vs. 29%; P = 0.048). The repeatability coefficient did not significantly differ between lesions with SUVpeak above or below the median value of 8.3 (19% vs. 28%; P = 0.264). Conclusion: The repeatability of SUVAUC was comparable to that of standard SUV. The repeatability coefficients of various semiquantitative 18F-fluoromethylcholine parameters (SUV, MTV, and total uptake in the lesion) were approximately 35%. Larger differences are likely to represent treatment effects.

Accuracy and Precision of Partial-Volume Correction in Oncological PET/CT Studies

Accurate quantification of tracer uptake in small tumors using PET is hampered by the partial-volume effect as well as by the method of volume-of-interest (VOI) delineation. This study aimed to investigate the effect of partial-volume correction (PVC) combined with several VOI methods on the accuracy and precision of quantitative PET. Methods: Four image-based PVC methods and resolution modeling (applied as PVC) were used in combination with several common VOI methods. Performance was evaluated using simulations, phantom experiments, and clinical repeatability studies. Simulations were based on a whole-body 18F-FDG PET scan in which differently sized spheres were placed in lung and mediastinum. A National Electrical Manufacturers Association NU2 quality phantom was used for the experiments. Repeatability data consisted of an 18F-FDG PET/CT study on 11 patients with advanced non–small cell lung cancer and an 18F-fluoromethylcholine PET/CT study on 12 patients with metastatic prostate cancer. Results: Phantom data demonstrated that most PVC methods were strongly affected by the applied resolution kernel, with accuracy differing by about 20%–50% between full-width-at-half-maximum settings of 5.0 and 7.5 mm. For all PVC methods, large differences in accuracy were seen among all VOI methods. Additionally, the image-based PVC methods were observed to have variable sensitivity to the accuracy of the VOI methods. For most PVC methods, accuracy was strongly affected by more than a 2.5-mm misalignment of true (simulated) VOI. When the optimal VOI method for each PVC method was used, high accuracy could be achieved. For example, resolution modeling for mediastinal lesions and iterative deconvolution for lung lesions were 99% ± 1.5% and 99% ± 0.9% accurate, respectively, for spheres 15–40 mm in diameter. Precision worsened slightly for resolution modeling and to a larger extent for some image-based PVC methods. Uncertainties in delineation propagated into uncertainties in PVC performance, as confirmed by the clinical data. Conclusion: The accuracy and precision of the tested PVC methods depended strongly on VOI method, resolution settings, contrast, and spatial alignment of the VOI. PVC has the potential to substantially improve the accuracy of tracer uptake assessment, provided that robust and accurate VOI methods become available. Commonly used delineation methods may not be adequate for this purpose.

Benefits of Using Stereotactic Body Radiotherapy in Patients With Metachronous Oligometastases of Hormone-Sensitive Prostate Cancer Detected by [18F]fluoromethylcholine PET/CT

Micro‐Abstract Stereotactic body radiation therapy (SBRT) might postpone the start of androgen deprivation therapy (ADT) in patients with oligometastatic recurrence of hormone‐sensitive prostate cancer. We included 43 SBRT‐treated patients, and a control cohort of 20 non–SBRT‐treated patients, in this retrospective study. Patients in the SBRT cohort could start ADT significantly later, and the time till castration resistance was significantly longer. Introduction: For patients with oligometastatic recurrence of prostate cancer (PC), stereotactic body radiation therapy (SBRT) represents an attractive treatment option, as it is safe without major side effects. The aim of this study was to investigate the impact of SBRT in delaying the start of androgen deprivation therapy (ADT). Patients and Methods: Forty‐three patients treated with SBRT for oligometastatic recurrence (< 5 metastases) of hormone‐sensitive PC, defined with [18F]fluoromethylcholine positron emission tomography/computed tomography were included. As a control group, 20 patients with oligometastatic disease not treated with SBRT were identified from another hospital. Data were collected retrospectively. Results: A post‐SBRT prostate‐specific antigen (PSA) response was seen in 29 (67.4%) of 43 patients. Median ADT–free survival (ADT‐FS) was 15.6 months (95% confidence interval [CI], 11.7‐19.5) for the whole group, and 25.7 months (95% CI, 9.0‐42.4) for patients with a PSA response. Seven patients were treated with a second course of SBRT because of oligometastatic disease recurrence; the ADT‐FS in this group was 32.1 months (95% CI, 7.8‐56.5). Compared with the control group, the ADT‐FS from first diagnosis of metastasis was significantly longer, with 17.3 (95% CI, 13.7‐20.9) months versus 4.19 months (95% CI, 0.0‐9.0), P < .001. Also, time between diagnosis of the metastasis until progression of disease during ADT use (castration resistance) was longer for the SBRT‐treated patients (mean 66.6, 95% CI, 53.5‐79.8, vs. 36.41, 95% CI, 26.0‐46.8 months, P = .020). There were no grade III or IV adverse events reported. Conclusion: SBRT can safely and effectively be used to postpone ADT in appropriately selected patients with oligometastatic recurrence of PC.

Letter: PET-guided stereotactic irradiation of prostate cancer lymph node metastases.

et al. correctly note, I did not address the disadvantages of labeled leukocyte imaging in the article. I assumed, perhaps mistakenly, that after more than 30 y of publications on labeled leukocyte imaging, it was unnecessary to reiterate the already well-known shortcomings of the procedure and that better use could be made of the allotted space. Kwee et al. suggest that the issue of contradictory results for 18F-FDG was based on one—in their opinion, flawed—investigation (2). To the contrary, contradictory results have been, and continue to be, reported for 18F-FDG alone and in combination with bone or labeled leukocyte imaging. These results, both favorable and unfavorable, were summarized in my article (1). Kwee et al. attribute the poor results of Love et al. (2) for 18F-FDG to the use of coincidence detection rather than dedicated PET. A careful review of the literature, however, reveals investigations that used state-of-the-art PET or PET/CT to diagnose prosthetic joint infection, and their results for 18F-FDG were no better, and in some cases were less satisfactory, than the results reported by Love et al. (1–4). Consequently, the argument that the data reported by Love et al. (2) are invalid, or flawed, because of the imaging device used is not tenable. Furthermore, this investigation was one of the very few in which the final diagnosis, in all cases, was based on histopathologic and microbiologic specimens obtained at the time of surgery (2). Finally, Kwee et al. mention that recent consensus guidelines do not include leukocyte/marrow imaging for detecting prosthetic joint infection. One can presume that these guidelines do not include 18F-FDG either, since Kwee et al. do not address this in their letter. According to the most recent revision of the American College of Radiology Appropriateness Criteria on imaging after total hip arthroplasty, labeled leukocyte/bone marrow imaging is the best imaging test for diagnosing infection (5). In summary, given the inconsistent and at times contradictory results that have been reported for 18F-FDG over more than 15 y of investigation, 18F-FDG—its practical advantages notwithstanding—is not a suitable replacement for labeled leukocyte/marrow imaging for diagnosing prosthetic joint infection. For the moment, labeled leukocyte/ marrow imaging is the best imaging test available for this indication.

[18F]Fluoromethylcholine as a Chemotherapy Response Read-Out in Prostate Cancer Cells

PurposeThe objective of the present study is to determine whether uptake of [18F]fluoromethylcholine ([18F]FCH) in comparison with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) accurately reflects chemotherapy efficacy at the tumor cell level in prostate cancer (PC).ProceduresThe effects of docetaxel and cabazitaxel on viable tumor cell number were explored in four PC cell lines. Cellular uptake of [18F]FDG and [18F]FCH was compared with the effects measured using sulforhodamine B (SRB) assay, cell counting and colony formation assay (CFA), as proximators of viable tumor cell number. Agreement between uptake and cell numbers was assessed by Bland-Altman plots.Results[18F]FCH uptake in all PC cell lines significantly correlated to the cell numbers surviving the respective drug concentrations. Bland-Altman analysis showed that [18F]FDG uptake resulted in signal overestimation and higher variability after chemotherapy.Conclusions[18F]FCH uptake correlates well with viable tumor cell numbers remaining after docetaxel and cabazitaxel exposure. Radiolabeled choline is a potential response monitoring biomarker after chemotherapy for PC.