PET Criteria by Cancer Type from Imaging Interpretation to Treatment Response Assessment: Beyond FDG PET Score.

BACKGROUND: in recent years, the role of positron emission tomography (PET) and PET/computed tomography (PET/CT) has emerged as a reliable diagnostic tool in a wide variety of pathological conditions. This review aims to collect and review PET criteria developed for interpretation and treatment response assessment in cases of non-[18F]fluorodeoxyglucose ([18F]FDG) imaging in oncology. METHODS: A wide literature search of the PubMed/MEDLINE, Scopus and Google Scholar databases was made to find relevant published articles about non-[18F]FDG PET response criteria. RESULTS: The comprehensive computer literature search revealed 183 articles. On reviewing the titles and abstracts, 149 articles were excluded because the reported data were not within the field of interest. Finally, 34 articles were selected and retrieved in full-text versions. CONCLUSIONS: available criteria are a promising tool for the interpretation of non-FDG PET scans, but also to assess the response to therapy and therefore to predict the prognosis. However, oriented clinical trials are needed to clearly evaluate their impact on patient management.

PSMA and Choline PET for the Assessment of Response to Therapy and Survival Outcomes in Prostate Cancer Patients: A Systematic Review from the Literature.

The aims of this systematic review were to (1) assess the utility of PSMA-PET and choline-PET in the assessment of response to systemic and local therapy, and to (2) determine the value of both tracers for the prediction of response to therapy and survival outcomes in prostate cancer. We performed a systematic literature search in PubMed/Scopus/Google Scholar/Cochrane/EMBASE databases (between January 2010 and October 2021) accordingly. The quality of the included studies was evaluated following the "Quality Assessment of Prognostic Accuracy Studies" tool (QUAPAS-2). We selected 40 articles: 23 articles discussed the use of PET imaging with [68Ga]PSMA-11 (16 articles/1123 patients) or [11C]/[18F]Choline (7 articles/356 patients) for the prediction of response to radiotherapy (RT) and survival outcomes. Seven articles (three with [68Ga]PSMA-11, three with [11C]Choline, one with [18F]Choline) assessed the role of PET imaging in the evaluation of response to docetaxel (as neoadjuvant therapy in one study, as first-line therapy in five studies, and as a palliative regimen in one study). Seven papers with radiolabeled [18F]Choline PET/CT (n = 121 patients) and three with [68Ga]PSMA-11 PET (n = 87 patients) were selected before and after enzalutamide/abiraterone acetate. Finally, [18F]Choline and [68Ga]PSMA-11 PET/CT as gatekeepers for the treatment of metastatic prostate cancer with Radium-223 were assessed in three papers. In conclusion, in patients undergoing RT, radiolabeled choline and [68Ga]PSMA-11 have an important prognostic role. In the case of systemic therapies, the role of such new-generation imaging techniques is still controversial without sufficient data, thus requiring additional in this scenario.

PET/MR in recurrent glioblastoma patients treated with regorafenib: [18F]FET and DWI-ADC for response assessment and survival prediction.

OBJECTIVE: The use of regorafenib in recurrent glioblastoma patients has been recently approved by the Italian Medicines Agency (AIFA) and added to the National Comprehensive Cancer Network (NCCN) 2020 guidelines as a preferred regimen. Given its complex effects at the molecular level, the most appropriate imaging tools to assess early response to treatment is still a matter of debate. Diffusion-weighted imaging and O-(2-18F-fluoroethyl)-L-tyrosine positron emission tomography ([18F]FET PET) are promising methodologies providing additional information to the currently used RANO criteria. The aim of this study was to evaluate the variations in diffusion-weighted imaging/apparent diffusion coefficient (ADC) and [18F]FET PET-derived parameters in patients who underwent PET/MR at both baseline and after starting regorafenib. METHODS: We retrospectively reviewed 16 consecutive GBM patients who underwent [18F]FET PET/MR before and after two cycles of regorafenib. Patients were sorted into stable (SD) or progressive disease (PD) categories in accordance with RANO criteria. We were also able to analyze four SD patients who underwent a third PET/MR after another four cycles of regorafenib. [18F]FET uptake greater than 1.6 times the mean background activity was used to define an area to be superimposed on an ADC map at baseline and after treatment. Several metrics were then derived and compared. Log-rank test was applied for overall survival analysis. RESULTS: Percentage difference in FET volumes correlates with the corresponding percentage difference in ADC (R = 0.54). Patients with a twofold increase in FET after regorafenib showed a significantly higher increase in ADC pathological volume than the remaining subjects (p = 0.0023). Kaplan-Meier analysis, performed to compare the performance in overall survival prediction, revealed that the percentage variations of FET- and ADC-derived metrics performed at least as well as RANO criteria (p = 0.02, p = 0.024 and p = 0.04 respectively) and in some cases even better. TBR Max and TBR mean are not able to accurately predict overall survival. CONCLUSION: In recurrent glioblastoma patients treated with regorafenib, [18F]FET and ADC metrics, are able to predict overall survival and being obtained from completely different measures as compared to RANO, could serve as semi-quantitative independent biomarkers of response to treatment. ADVANCES IN KNOWLEDGE: Simultaneous evaluation of [18F]FET and ADC metrics using PET/MR allows an early and reliable identification of response to treatment and predict overall survival.

10-Year Clinical Experience With 18F-Choline PET/CT: An Italian Multicenter Retrospective Assessment of 3343 Patients.

PURPOSE: The primary aim of this multicenter retrospective analysis is to examine the role of F-choline PET/CT as a diagnostic tool for staging and restaging prostate cancer (PCa) in a large population in the light of 10 years of clinical experience. A secondary aim of the study is to produce data on the predictors of a positive F-choline PET/CT result in the setting of PCa primaries and biochemical recurrences. MATERIALS AND METHODS: This multicenter retrospective cohort study is based on data collected by 9 Italian nuclear medicine departments. Between October 2008 and September 2019, 3343 men underwent F-choline PET/CT scans before receiving definitive treatments for a primary PCa or biochemical recurrence. Inclusion criteria were (1) histologically proven PCa (on surgical specimens or prostate biopsies from patients not treated surgically) and (2) availability of clinical and pathological data, including serum prostate specific antigen (PSA) level at the time of PET/CT scanning. RESULTS: F-choline PET/CT was performed in 545 cases (16.4%) for cancer staging and in 2798 (83.6%) for restaging purposes, and the result was positive in 540 (99.1%) for the former and 1993 (71.2%) for the latter. A positive PET/CT result was always associated with a high Gleason score (>7) and high PSA levels (P < 0.01). The percentage of patients with a PSA threshold less than 1.0 ng/mL for performing PET/CT was higher in the years 2014 to 2019 (n = 341, 25% of cases) than during the previous period (n = 148, 16%; in 2008-2013). When used for staging purposes, receiver operating characteristic analysis showed that PSA levels of 9.2, 16.4, and 16.6 ng/mL were the optimal cutoffs for distinguishing between positive and negative PET/CT findings for local disease, lymph node involvement, and metastasis, respectively. In the restaging setting, a PSA level of 1.27 ng/mL was the optimal cutoff for distinguishing between a positive and negative PET/CT scan. CONCLUSIONS: F-choline PET/CT can help identify early recurrences, even in the case of low PSA levels (<1 ng/mL). Our data suggest that important improvements have been made in the interpretation of F-choline images and in patient selection in the last 5 years.

Italian Tailored Assessment of Lung Indeterminate Accidental Nodule by Proposing a Segmental Pet/Computed Tomography (s-Pet/Ct): Rationale And Study Design of a Retrospective, Multicenter Trial.

BACKGROUND: The Italian Tailored Assessment of Lung Indeterminate Accidental Nodule (ITALIAN) is a retrospective, multicenter trial designed to compare the diagnostic information provided by segmental positron emission tomography (PET)/computed tomography (CT) (s-PET/CT) with those of whole body (wb)-PET/CT in patients with single pulmonary nodules (SPN). This report describes the details and implications of the ITALIAN trial design. METHODS AND RESULTS: Between September 2016 and May 2017, 502 consecutive patients (302 men, mean age 67±12 years) with SPN undergoing 18F-fluorodeoxyglucose (FDG) PET/CT were enrolled. PET/CT images will be visually and semiquantitatively evaluated. For visual analysis, a 4-point scoring system (1=absent; 2=mild; 3=moderate and 4=intense) will be used; for semiquantitative analysis, maximum standardized uptake value (SUV) in the SPN and mean SUV in the mediastinal blood pool and in the liver will be computed. CONCLUSION: The results of this trial might help to define the role of s-PET/CT in patients with SPN. This trial will also evaluate the impact on radiobiology and costs subsequent the introduction of this alternative imaging acquisition modality.

Economic burden of the management of metastatic castrate-resistant prostate cancer in Italy: a cost of illness study.

BACKGROUND: Prostate cancer (PCa) accounts for 20% of all cancers in subjects over 50 years in Italy. The majority of patients with PCa present with localized disease at the time of diagnosis, but many patients develop recurrent metastatic disease after treatment with curative intent. Androgen deprivation therapy is the standard of care for metastatic PCa patients; unfortunately, most of them progress to castrate-resistant prostate cancer (CRPC) within 5 years. Metastatic CRPC (mCRPC) heavily affects patients in terms of quality of life, side effects, and survival, and greatly impacts economic costs. The approval of new effective agents in recent years, including cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, has dramatically changed patient management. MATERIALS AND METHODS: Here, we aimed to estimate the current costs of illness of mCRPC in Italy. All patients affected by mCRPC and treated with a single agent in an annual time horizon were considered. Therefore, the analysis was not focused on the management pathway of single patients through different lines of treatment. Direct medical costs referred to therapy, adverse event management, and skeletal-related event management were analyzed. A bottom-up approach was used to estimate the resource consumption: through national guidelines and expert opinions, the mean cost per patient was estimated and then multiplied by the total number of patients diagnosed with mCRPC. RESULTS: Direct medical costs ranged from €196.5 million to €228.0 million, representing ~0.2% of the financing of the Italian National Health Service in 2016. The main cost driver was the cost of treatment, which represented more than 77% of the overall economic burden. CONCLUSION: Our analysis, reflective of real clinical practice, shows for the first time the high economic cost of mCRPC in Italy.

Alternative imaging strategy of solitary pulmonary nodule by FDG PET/CT: Can be imagined a tailored PET?

OBJECTIVE: Patients with solitary pulmonary nodule (SPN) are usually sent to total-body positron emission tomography/computed tomography (PET/CT) examination with 18F-fluorodeoxyglucose (FDG). However, a segmental scan strategy may improve cost/effectiveness in this category of patients. CONCLUSION: A segmental PET/CT scan only at the chest level could be performed in patients with indeterminate SPN. Limiting the PET/CT field to the thoracic region would greatly affect on radiobiology, department organization and health-care costs.

Clinical results and economic considerations of 68Ga-PSMA and radiolabeled choline in prostate cancer.

In recent years there was an impressive improvement in the options for the management of patients with prostate cancer. Nuclear Medicine has significantly enriched its diagnostic options, both in radiopharmacy and in instrumentation, in order to accurately target prostatic cancer cells, thus rendering the physicians able to adopt the best therapeutic strategy. In the present analysis, we have evaluated the available published data about 68Ga-PSMA and radio-labeled choline, two radiopharmaceutical agents for positron emission tomography/computed tomography (PET/CT) examination, by reporting clinical information and considering data about legal, economic and organization aspects.

Conflicting or complementary role of computed tomography (CT) and positron emission tomography (PET)/CT in the assessment of thymic cancer and thymoma: our experience and literature review.

BACKGROUND: To evaluate the role of computed tomography (CT) and positron emission tomography (PET)/CT in patients with thymic cancer and thymoma at initial staging. METHODS: We retrospectively reviewed CT and PET/CT scans of 26 patients with a thymic cancer (n = 9) or thymoma (n = 17). Chest CT findings documented were qualitative and quantitative. Both qualitative and semiquantitative data were recovered by PET/CT. The comparisons among histological entities, outcome, and qualitative data from CT and PET/CT were made by non-parametric analysis. RESULTS: PET/CT resulted positive in 15/17 patients with thymoma. CT was available in 5/9 (56%) patients with thymic cancer and in 3/17 with thymoma. All quantitative CT parameters were significantly higher in patients with thymic cancer than thymoma (maximum axial diameter: 45 vs. 20 mm, maximum longitudinal diameter: 69 vs. 21 mm and volume: 77.91 vs. 4.52 mL; all P < 0.05). Conversely, only metabolic tumor volume (MTV) and total lesion glycolysis were significantly different in patients with thymic cancer than thymoma (126.53 vs. 6.03 cm3 and 246.05 vs. 20.32, respectively; both P < 0.05). After a median follow-up time of 17.45 months, four recurrences of disease occurred: three in patients with thymic cancer and one with a type B2 thymoma. CT volume in patients with recurrent disease was 102.19 mL versus a median value of 62.5 mL in six disease-free patients. MTV was higher in the recurrent than disease-free patient subset (143.3 vs. 81.13 cm(3)), although not statistically significant (P = 0.075). CONCLUSION: Our preliminary results demonstrated that both morphological and metabolic volume could be useful from a diagnostic and prognostic point of view in thymic cancer and thymoma patients. A large multi-center clinical trial experience for confirming the findings of this study seems mandatory.

Risk stratification and prognostic assessment by myocardial perfusion-gated SPECT in patients with left bundle-branch block and low-intermediate cardiac risk.

OBJECTIVE: In high-risk patients with left bundle-branch block (LBBB), functional but not perfusion parameters yield incremental prognostic information. The aim of our study was to evaluate the prognostic value of gated single photon emission computed tomography (SPECT) in low-intermediate risk LBBB patients. METHODS: One hundred seventy-six subjects underwent stress-rest dual-day protocol 99mTc sestamibi-gated SPECT and were dichotomized in two groups: without LBBB (Group 1, n = 86) and with LBBB (Group 2, n = 90). Patients were followed for 32 ± 18 months. Cox regression multivariate analysis was used to determine which variable was the best predictor of cardiac event. Event-free survival curves were computed by Kaplan-Meier method. RESULTS: Myocardial perfusion scintigraphy was abnormal in 32 and 60 patients for Groups 1 and 2, respectively (37 vs. 67 %, p < 0.001). In Groups 1 and 2, the mean summed stress score (SSS) was 3.7 ± 5.6 versus 6.7 ± 6.4, while the mean summed difference score (SDS) was 1.6 ± 2.5 versus 2.7 ± 3.3 (both p < 0.005); therefore 34 % of patients in Group 1 and 53 % of those in Group 2 presented myocardial ischemia. All functional parameters were significantly different between the two subsets (all p < 0.005). Follow-up was completed in 161 patients (92 %); 10 events occurred in Group 1 and 20 in Group 2 (14 vs. 25 %). The event-free survival was significantly higher in patients with normal than in those with abnormal scan (85 vs. 63 %, p < 0.005); moreover, the prognosis of patients with LBBB was significantly worse. At multivariate analysis, SDS was found to be the only independent predictor of cardiac events both in all patients and in LBBB population (HR 3.08, and HR 4.99, p < 0.05). CONCLUSIONS: This is the first study to assess the prognostic value of gated SPECT in patients with LBBB and low-intermediate cardiac risk. Both perfusion and functional data obtained by gated SPECT are different between patients with and without LBBB. However, SDS is the only predictor of events. Thus, the amount of reversible ischemia at gated SPECT has a discriminative power in stratifying the cardiac risk of LBBB population.

Myocardial perfusion imaging and risk classification for coronary heart disease in diabetic patients. The IDIS study: a prospective, multicentre trial.

PURPOSE: To determine whether stress-rest myocardial perfusion single-photon emission (MPS) computed tomography improves coronary heart disease (CHD) risk classification in diabetic patients. METHODS: In 822 consecutive diabetic patients, risk estimates for a CHD event were categorized as 0% to <3%, 3% to <5%, and ≥5% per year using Cox proportional hazards models. Model 1 used traditional CHD risk factors and electrocardiography (ECG) stress test data and model 2 used these variables plus MPS imaging data. We calculated the net reclassification improvement (NRI) and compared the distribution of risk using model 2 vs. model 1. CHD death, myocardial infarction and unstable angina requiring coronary revascularization were the outcome measures. RESULTS: During follow-up (58 ± 11 months), 148 events occurred. Model 2 improved risk prediction compared to model 1 (NRI 0.25, 95% confidence interval, CI, 0.15-0.34; p < 0.001). Overall, 301 patients were reclassified to a higher risk category, with an event rate of 28%, and 26 to a lower risk category, with an event rate of 15%. Among patients at 3% to <5% risk, 53% were reclassified at higher risk and 25% at lower risk (NRI 0.42, 95% CI 0.07-0.76; p < 0.05). The cost per NRI was $880.80 for MPS imaging as compared to an outpatient visit with an ECG stress test. CONCLUSION: The addition of MPS imaging data to a prediction model based on traditional risk factors and ECG stress test data significantly improved CHD risk classification in patients with diabetes.

Impact of inducible ischemia by stress SPECT in cardiac risk assessment in diabetic patients: rationale and design of a prospective, multicenter trial.

BACKGROUND: A prospective, multicenter trial has been designed to evaluate the impact of inducible ischemia by stress single photon emission computed tomography (SPECT) in diabetic patients and to define the role of SPECT in assessing the cardiac risk in such patients. This report presents the details and implications of the Impact of Inducible Ischemia by Stress SPECT (IDIS) trial design. METHODS AND RESULTS: Between January 2002 and September 2005, 1006 consecutive patients (649 men and 357 women; mean age, 63 +/- 9 years) with at least a 5-year history of type 2 diabetes mellitus were enrolled. All patients underwent stress-rest sestamibi SPECT imaging with physical exercise (n = 573) or dipyridamole (n = 433). SPECT studies will be analyzed by use of a 17-segment scoring system to calculate left ventricular ejection fraction, summed stress score, summed rest score, and summed difference score. The SPECT study will be considered abnormal if the summed stress score is 3 or greater. Patients with abnormal studies will be considered to have ischemia if the summed difference score is 2 or greater. CONCLUSION: The results of this trial should help to define the role of SPECT in assessing cardiac risk in diabetic patients. Furthermore, this trial will prospectively evaluate subsequent patient outcome during long-term follow-up.