¹⁸F-fluoride positron emission tomography/computed tomography and bone scintigraphy for diagnosis of bone metastases in newly diagnosed, high-risk prostate cancer patients:study protocol for a multicentre, diagnostic test accuracy study

BACKGROUND: For decades, planar bone scintigraphy has been the standard practice for detection of bone metastases in prostate cancer and has been endorsed by recent oncology/urology guidelines. It is a sensitive method with modest specificity. (18)F-fluoride positron emission tomography/computed tomography has shown improved sensitivity and specificity over bone scintigraphy, but because of methodological issues such as retrospective design and verification bias, the existing level of evidence with (18)F-fluoride positron emission tomography/computed tomography is limited. The primary objective is to compare the diagnostic properties of (18)F-fluoride positron emission tomography/computed tomography versus bone scintigraphy on an individual patient basis. METHODS/DESIGN: One hundred forty consecutive, high-risk prostate cancer patients will be recruited from several hospitals in Denmark. Sample size was calculated using Hayen’s method for diagnostic comparative studies. This study will be conducted in accordance with recommendations of standards for reporting diagnostic accuracy studies. Eligibility criteria comprise the following: 1) biopsy-proven prostate cancer, 2) PSA ≥50 ng/ml (equals a prevalence of bone metastasis of ≈ 50 % in the study population on bone scintigraphy), 3) patients must be eligible for androgen deprivation therapy, 4) no current or prior cancer (within the past 5 years), 5) ability to comply with imaging procedures, and 6) patients must not receive any investigational drugs. Planar bone scintigraphy and (18)F-fluoride positron emission tomography/computed tomography will be performed within a window of 14 days at baseline. All scans will be repeated after 26 weeks of androgen deprivation therapy, and response of individual lesions will be used for diagnostic classification of the lesions on baseline imaging among responding patients. A response is defined as PSA normalisation or ≥80 % reduction compared with baseline levels, testosterone below castration levels, no skeletal related events, and no clinical signs of progression. Images are read by blinded nuclear medicine physicians. The protocol is currently recruiting. DISCUSSION: To the best of our knowledge, this is one of the largest prospective studies comparing (18)F-fluoride positron emission tomography/computed tomography and bone scintigraphy. It is conducted in full accordance with recommendations for diagnostic accuracy trials. It is intended to provide valid documentation for the use of (18)F-fluoride positron emission tomography/computed tomography for examination of bone metastasis in the staging of prostate cancer

Reporting and Handling of Indeterminate Bone Scan Results in the Staging of Prostate Cancer:A Systematic Review

Bone scintigraphy is key in imaging skeletal metastases in newly diagnosed prostate cancer. Unfortunately, a notable proportion of scans are not readily classified as positive or negative but deemed indeterminate. The extent of reporting of indeterminate bone scans and how such scans are handled in clinical trials are not known. A systematic review was conducted using electronic databases up to October 2016. The main outcome of interest was the reporting of indeterminate bone scans, analyses of how such scans were managed, and exploratory analyses of the association of study characteristics and the reporting of indeterminate bone scan results. Seventy-four eligible clinical trials were identified. The trials were mostly retrospective (85%), observational (95%), large trials (median 195 patients) from five continents published over four decades. The majority of studies had university affiliation (72%), and an author with imaging background (685). Forty-five studies (61%) reported an indeterminate option for the bone scan and 23 studies reported the proportion of indeterminate scans (median 11.4%). Most trials (44/45, 98%) reported how to handle indeterminate scans. Most trials (n = 39) used add-on supplementary imaging, follow-up bone scans, or both. Exploratory analyses showed a significant association of reporting of indeterminate results and number of patients in the study (p = 0.024) but failed to reach statistical significance with other variables tested. Indeterminate bone scan for staging of prostate cancer was insufficiently reported in clinical trials. In the case of indeterminate scans, most studies provided adequate measures to obtain the final status of the patients

Added value of 68Ga-PSMA PET/CT for the detection of bone metastases in patients with newly diagnosed prostate cancer and a previous 99mTc bone scintigraphy

PURPOSE To investigate the added value and diagnostic accuracy of 68Ga-PSMA PET/CT versus bone scintigraphy (BS) for bone metastasis detection at the primary staging of prostate cancer (PCa). METHODS Inclusion criteria involved consecutive patients with newly diagnosed intermediate- to high-risk PCa, who had undergone BS, mostly with supplementary SPECT/low-dose CT, and 68Ga-PSMA-11 PET/CT within less than 3 months without therapy initiation between the two investigations. BS was evaluated according to clinical routine and reported as no bone metastases (M0), bone metastases (M1), or equivocal (Me). The 68Ga-PSMA-11 PET/CT was blindly evaluated by three specialists as M0, M1, or Me at the patient level. Sensitivity analyses were conducted using a "best valuable comparator" using all available imaging and clinical follow-up as a reference. RESULTS In total, 112 patients were included; 68Ga-PSMA-11 PET/CT showed a sensitivity of 1.00, specificity of 0.93-0.96, positive predictive value of 0.74-0.81, and negative predictive value of 1.00. 68Ga-PSMA-11 PET/CT revealed bone metastases in 8 of 81 patients with M0 disease according to BS. 68Ga-PSMA-11 PET/CT confirmed the presence of bone metastases in all patients (n = 9) with M1 disease according to BS. In patients with Me by BS, 68Ga-PSMA PET/CT provided a definite result in 20 of 22 patients. 68Ga-PSMA-11 PET/CT resulted in a false-positive answer in four patients with solitary rib lesions. CONCLUSION 68Ga-PSMA-11 PET/CT revealed bone metastases in 10% of patients without bone metastases on BS and in 36% patients with indeterminate BS. However, solitary PSMA-avid lesions in the ribs should be interpreted cautiously as they may represent false-positive findings

Influence of Prior Imaging Information on Diagnostic Accuracy for Focal Skeletal Processes-A Retrospective Analysis of the Consistency between Biopsy-Verified Imaging Diagnoses

Introduction: Comparing imaging examinations with those previously obtained is considered mandatory in imaging guidelines. To our knowledge, no studies are available on neither the influence, nor the sequence, of prior imaging and reports on diagnostic accuracy using biopsy as the reference standard. Such data are important to minimize diagnostic errors and to improve the preparation of diagnostic imaging guidelines. The aim of our study was to provide such data. Materials and methods: A retrospective cohort of 216 consecutive skeletal biopsies from patients with at least 2 different imaging modalities (X-ray, CT and MRI) performed within 6 months of biopsy was identified. The diagnostic accuracy of the individual imaging modality was assessed. Finally, the possible influence of the sequence of imaging modalities was investigated. Results: No significant difference in the accuracy of the imaging modalities was shown, being preceded by another imaging modality or not. However, the sequence analyses indicate sequential biases, particularly if MRI was the first imaging modality. Conclusion: The sequence of the imaging modalities seems to influence the diagnostic accuracy against a pathology reference standard. Further studies are needed to establish evidence-based guidelines for the strategy of using previous imaging and reports to improve diagnostic accuracy

Use of 18F-NaF PET in the staging of skeletal metastases of newly diagnosed, high-risk prostate cancer patients:a nationwide cohort study

OBJECTIVE: To determine whether preoperative staging of high-risk prostate cancer with (18)F-sodium-fluoride ((18)F-NaF) positron emission tomography (PET) reduces the risk of skeletal metastases. DESIGN: Nationwide, population-based cohort study using real-world data. SETTING: The study used national health registries, including all sites in Denmark from 2011 to 2018. PARTICIPANTS: Newly diagnosed high-risk prostate cancer patients who underwent radical prostatectomy from 2011 to 2018. Patients were stratified into two groups according to the preoperative imaging modality of either (18)F-NaF PET or bone scintigraphy. MAIN OUTCOME MEASURES: The risk of skeletal-related events (SREs) as a proxy for skeletal metastases following radical prostatectomy. The secondary endpoint was overall survival. RESULTS: Between 1 January 2011 and 31 December 2018, 4183 high-risk patients underwent radical prostatectomy. Of these patients, 807 (19.3%) underwent (18)F-NaF PET and 2161 (51.7%) underwent bone scintigraphy. The remaining 30% were examined by a different imaging method or did not undergo imaging. Using the inverse probability of treatment weighting to control potential confounding, the HR of experiencing an SRE for patients in the (18)F-NaF PET group versus the bone scintigraphy group was 1.15 (95% CI 0.86 to 1.54). The 3-year survival rates were 97.4% (95% CI 96.1 to 98.7) and 97.1% (95% CI 96.4 to 97.9) for patients receiving (18)F-NaF PET and bone scintigraphy, respectively. CONCLUSION: Patients with high-risk prostate cancer undergoing preoperative staging with (18)F-NaF PET did not display a lower risk of developing SREs after prostatectomy compared with patients undergoing bone scintigraphy. The survival rates were similar between the two groups

Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease

Background Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease. Methods and Findings We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time. The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66). Conclusion Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research