Multicenter survey of PET/CT protocol parameters that affect standardized uptake values.

Clinical trials that evaluate cancer treatments may benefit from positron emission tomography (PET) imaging, which for many cancers can discriminate between effective and ineffective treatments. However, the image metrics used to quantify disease and evaluate treatment may be biased by many factors related to clinical protocols and PET system settings, many of which are site- and/or manufacturer-specific. An observational study was conducted using two surveys that were designed to record key sources of bias and variability in PET imaging. These were distributed to hospitals across the United States. The first round of surveys was designed and distributed by the American College of Radiology's Centers of Quantitative Imaging Excellence program in 2011. The second survey expanded on the first and was completed by the National Cancer Institute's Quantitative Imaging Network. Sixty-three sites responded to the first survey and 36 to the second. Key imaging parameters varied across participating sites. The range of reported methods for image acquisition and reconstruction suggests that signal biases are not matched between sites. Patient preparation was also inconsistent, potentially contributing additional variability. For multicenter clinical trials, efforts to control biases through standardization of imaging procedures should precede patient measurements.

Optimal FDG PET/CT volumetric parameters for risk stratification in patients with locally advanced non-small cell lung cancer: results from the ACRIN 6668/RTOG 0235 trial.

PURPOSE: In recent years, multiple studies have demonstrated the value of volumetric FDG-PET/CT parameters as independent prognostic factors in patients with non-small cell lung cancer (NSCLC). We aimed to determine the optimal cut-off points of pretreatment volumetric FDG-PET/CT parameters in predicting overall survival (OS) in patients with locally advanced NSCLC and to recommend imaging biomarkers appropriate for routine clinical applications. METHODS: Patients with inoperable stage IIB/III NSCLC enrolled in ACRIN 6668/RTOG 0235 were included. Pretreatment FDG-PET scans were quantified using semiautomatic adaptive contrast-oriented thresholding and local-background partial-volume-effect-correction algorithms. For each patient, the following indices were measured: metabolic tumor volume (MTV), total lesion glycolysis (TLG), SUVmax, SUVmean, partial-volume-corrected TLG (pvcTLG), and pvcSUVmean for the whole-body, primary tumor, and regional lymph nodes. The association between each index and patient outcome was assessed using Cox proportional hazards regression. Optimal cut-off points were estimated using recursive binary partitioning in a conditional inference framework and used in Kaplan-Meier curves with log-rank testing. The discriminatory ability of each index was examined using time-dependent receiver operating characteristic (ROC) curves and corresponding area under the curve (AUC(t)). RESULTS: The study included 196 patients. Pretreatment whole-body and primary tumor MTV, TLG, and pvcTLG were independently prognostic of OS. Optimal cut-off points were 175.0, 270.9, and 35.5 cm3 for whole-body TLG, pvcTLG, and MTV, and were 168.2, 239.8, and 17.4 cm3 for primary tumor TLG, pvcTLG, and MTV, respectively. In time-dependent ROC analysis, AUC(t) for MTV and TLG were uniformly higher than that of SUV measures over all time points. Primary tumor and whole-body parameters demonstrated similar patterns of separation for those patients above versus below the optimal cut-off points in Kaplan-Meier curves and in time-dependent ROC analysis. CONCLUSION: We demonstrated that pretreatment whole-body and primary tumor volumetric FDG-PET/CT parameters, including MTV, TLG, and pvcTLG, are strongly prognostic for OS in patients with locally advanced NSCLC, and have similar discriminatory ability. Therefore, we believe that, after validation in future trials, the derived optimal cut-off points for primary tumor volumetric FDG-PET/CT parameters, or their more refined versions, could be incorporated into routine clinical practice, and may provide more accurate prognostication and staging based on tumor metabolic features.

Performance Observations of Scanner Qualification of NCI-Designated Cancer Centers: Results From the Centers of Quantitative Imaging Excellence (CQIE) Program.

We present an overview of the Centers for Quantitative Imaging Excellence (CQIE) program, which was initiated in 2010 to establish a resource of clinical trial-ready sites within the National Cancer Institute (NCI)-designated Cancer Centers (NCI-CCs) network. The intent was to enable imaging centers in the NCI-CCs network capable of conducting treatment trials with advanced quantitative imaging end points. We describe the motivations for establishing the CQIE, the process used to initiate the network, the methods of site qualification for positron emission tomography, computed tomography, and magnetic resonance imaging, and the results of the evaluations over the subsequent 3 years.

Qualification of National Cancer Institute-Designated Cancer Centers for Quantitative PET/CT Imaging in Clinical Trials.

The National Cancer Institute developed the Centers for Quantitative Imaging Excellence (CQIE) initiative in 2010 to prequalify imaging facilities at all of the National Cancer Institute-designated comprehensive and clinical cancer centers for oncology trials using advanced imaging techniques, including PET. Here we review the CQIE PET/CT scanner qualification process and results in detail. Methods: Over a period of approximately 5 y, sites were requested to submit a variety of phantoms, including uniform and American College of Radiology-approved phantoms, PET/CT images, and examples of clinical images. Submissions were divided into 3 distinct time periods: initial submission (T0) and 2 requalification submissions (T1 and T2). Images were analyzed using standardized procedures, and scanners received a pass or fail designation. Sites had the opportunity to submit new data for scanners that failed. Quantitative results were compared across scanners within a given time period and across time periods for a given scanner. Results: Data from 65 unique PET/CT scanners across 56 sites were submitted for CQIE T0 qualification; 64 scanners passed the qualification. Data from 44 (68%) of those 65 scanners were submitted for T2. From T0 to T2, the percentage of scanners passing the CQIE qualification on the first attempt rose from 38% for T1 to 67% for T2. The most common reasons for failure were SUV outside specifications, incomplete submission, and uniformity issues. Uniform phantom and American College of Radiology-approved phantom results between scanner manufacturers were similar. Conclusion: The results of the CQIE process showed that periodic requalification may decrease the frequency of deficient data submissions. The CQIE project also highlighted the concern within imaging facilities about the burden of maintaining different qualifications and accreditations. Finally, for quantitative imaging-based trials, further evaluation of the relationships between the level of the qualification (e.g., bias or precision) and the quality of the image data, accrual rates, and study power is needed.

Radiopharmaceutical Options for the Ventilation Part of Ventilation-Perfusion Scintigraphy Performed for the Indication of Pulmonary Embolism: US Practice Survey.

PURPOSE: This US survey aimed to determine (1) relative utilization of the 2 techniques, a gas radiopharmaceutical technique (GRT) versus aerosolized radiopharmaceutical technique (ART), in ventilation-perfusion scintigraphy done for pulmonary embolism indication and (2) radiopharmaceuticals (RFs) used. PATIENTS AND METHODS: Nuclear medicine physicians and technologists were sent a questionnaire asking which RF(s) their imaging facilities are using for ventilation imaging. Respondents were classified as reporting from academic/teaching facilities (ATFs) or from community-based facilities (CBFs). RESULTS: Of the 256 surveyed, 78 responded (30.5%), who reported about 158 facilities. Majority (90/158, 57%) were CBFs, whereas the rest (68/158, 43%) were ATFs. Overall, slight majority (92/158, 58%) used ART, 90 using (99m)Tc-DTPA, one using (99m)Tc-sulfur colloid (SC), and one using (99m)Tc-PYP. Minority (66/158, 42%) used GRT (all ¹³³Xe). In the CBFs, a slight majority (55/90, 61%) used ART (including one that used (99m)Tc-PYP), whereas the rest 35 (39%) of 90 used GRT. In the ATFs, a slight majority (37/68, 54.4%) used ART (including 1 facility that used (99m)Tc-SC), whereas the rest (31/68, 45.6%) used GRT. There was no statistically significant difference in ART:GRT ratios between CBFs and ATFs (P = 0.35). CONCLUSIONS: Aerosolized RF technique is overall more common (57%) than GRT, about the same at CBFs and at ATFs, and almost all ART using (99m)Tc-DTPA. Therefore, (99m)Tc-DTPA price increase would have impacted a significant number of the US facilities, which should increase interest in alternatives identified by this survey­(99m)Tc-SC and (99m)Tc-PYP.

Metabolic tumor volume as a prognostic imaging-based biomarker for head-and-neck cancer: pilot results from Radiation Therapy Oncology Group protocol 0522.

PURPOSE: To evaluate candidate fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging biomarkers for head-and-neck chemoradiotherapy outcomes in the cooperative group trial setting. METHODS AND MATERIALS: Radiation Therapy Oncology Group (RTOG) protocol 0522 patients consenting to a secondary FDG-PET/CT substudy were serially imaged at baseline and 8 weeks after radiation. Maximum standardized uptake value (SUVmax), SUV peak (mean SUV within a 1-cm sphere centered on SUVmax), and metabolic tumor volume (MTV) using 40% of SUVmax as threshold were obtained from primary tumor and involved nodes. RESULTS: Of 940 patients entered onto RTOG 0522, 74 were analyzable for this substudy. Neither high baseline SUVmax nor SUVpeak from primary or nodal disease were associated with poor treatment outcomes. However, primary tumor MTV above the cohort median was associated with worse local-regional control (hazard ratio 4.01, 95% confidence interval 1.28-12.52, P=.02) and progression-free survival (hazard ratio 2.34, 95% confidence interval 1.02-5.37, P=.05). Although MTV and T stage seemed to correlate (mean MTV 6.4, 13.2, and 26.8 for T2, T3, and T4 tumors, respectively), MTV remained a strong independent prognostic factor for progression-free survival in bivariate analysis that included T stage. Primary MTV remained prognostic in p16-associated oropharyngeal cancer cases, although sample size was limited. CONCLUSION: High baseline primary tumor MTV was associated with worse treatment outcomes in this limited patient subset of RTOG 0522. Additional confirmatory work will be required to validate primary tumor MTV as a prognostic imaging biomarker for patient stratification in future trials.

Clinical trials in molecular imaging: the importance of following the protocol.

Nuclear medicine technologists and investigators who perform imaging procedures in clinical trials often have not received training on clinical research regulations, such as Title 21, part 312, of the Code of Federal Regulations or Good Clinical Practices. These regulations directly affect implementation of the therapeutic or imaging protocol. Lack of understanding of the regulatory expectations in clinical research can lead to unintended errors or omissions in critical data that are needed for development of a new drug. One common error is not following the protocol exactly as written, or modifying the imaging parameters in some way as to make the data nonstandard from site to site. These errors and omissions are a source of delay in the development of new imaging and therapeutic products. Although not following the protocol does not result in criminal penalties per se, errors and omissions can lead to regulatory consequences such as warning letters to the investigator or sponsor, which if not resolved can lead to barring a site or investigator from participation in any future research trials. Pharmaceutical sponsors, device sponsors, and federal granting agencies such as the National Cancer Institute enter into contracts with imaging sites under the expectation that the investigator and all research staff know and understand clinical research regulations. This article is intended to teach imaging personnel what any sponsor (pharmaceutical, device, or federal agency) is expecting from research imaging and how lack of understanding of Good Clinical Practices and federal regulations can impede the optimal success of a research study. After reading this article, nuclear medicine technologists should be able to understand the importance of following the clinical trial protocol to exact specifications, create a list of questions that should be answered by the sponsor or trial organizers before patient enrollment, describe Form FDA 1572, and describe the terms protocol, protocol deviation, protocol violation, and protocol exception.