Somali Gavane

Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer

BACKGROUND Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium-iodide symporter and uptake of iodine. Their effects in humans are not known. METHODS We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib. RESULTS Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia. CONCLUSIONS Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).

Practical Approach for Comparative Analysis of Multilesion Molecular Imaging Using a Semiautomated Program for PET/CT

We propose a standardized approach to quantitative molecular imaging (MI) in cancer patients with multiple lesions. Methods: Twenty patients with castration-resistant prostate cancer underwent 18F-FDG and 18F-16β-fluoro-5-dihydrotestosterone (18F-FDHT) PET/CT scans. Using a 5-point confidence scale, 2 readers interpreted coregistered scan sets on a workstation. Two hundred three sites per scan (specified in a lexicon) were reviewed. 18F-FDG–positive lesion bookmarks were propagated onto 18F-FDHT studies and then manually accepted or rejected. Discordance-positive 18F-FDHT lesions were similarly bookmarked. Lesional SUVmax was recorded. Tracer- and tissue-specific background correction factors were calculated via receiver-operating-characteristic analysis of 65 scan sets. Results: Readers agreed on more than 99% of 18F-FDG– and 18F-FDHT–negative sites. Positive-site agreement was 83% and 85%, respectively. Consensus-lesion maximum standardized uptake value (SUVmax) was highly reproducible (concordance correlation coefficient > 0.98). Receiver-operating-characteristic curves yielded 4 correction factors (SUVmax 1.8–2.6). A novel scatterplot (Larson-Fox-Gonen plot) depicted tumor burden and change in SUVmax for response assessments. Conclusion: Multilesion molecular imaging is optimized with a 5-step approach incorporating a confidence scale, site lexicon, semiautomated PET software, background correction, and Larson-Fox-Gonen graphing.

Positron emission tomography (PET) evaluation after initial chemotherapy and radiation therapy predicts local control in rhabdomyosarcoma.

PURPOSE 18-fluorodeoxyglucose positron emission tomography (PET) is already an integral part of staging in rhabdomyosarcoma. We investigated whether primary-site treatment response characterized by serial PET imaging at specific time points can be correlated with local control. PATIENTS AND METHODS We retrospectively examined 94 patients with rhabdomyosarcoma who received initial chemotherapy 15 weeks (median) before radiotherapy and underwent baseline, preradiation, and postradiation PET. Baseline PET standardized uptake values (SUVmax) and the presence or absence of abnormal uptake (termed PET-positive or PET-negative) both before and after radiation were examined for the primary site. Local relapse-free survival (LRFS) was calculated according to baseline SUVmax, PET-positive status, and PET-negative status by the Kaplan-Meier method, and comparisons were tested with the log-rank test. RESULTS The median patient age was 11 years. With 3-year median follow-up, LRFS was improved among postradiation PET-negative vs PET-positive patients: 94% vs 75%, P=.02. By contrast, on baseline PET, LRFS was not significantly different for primary-site SUVmax≤7 vs >7 (median), although the findings suggested a trend toward improved LRFS: 96% for SUVmax≤7 vs 79% for SUVmax>7, P=.08. Preradiation PET also suggested a statistically insignificant trend toward improved LRFS for PET-negative (97%) vs PET-positive (81%) patients (P=.06). CONCLUSION Negative postradiation PET predicted improved LRFS. Notably, 77% of patients with persistent postradiation uptake did not experience local failure, suggesting that these patients could be closely followed up rather than immediately referred for intervention. Negative baseline and preradiation PET findings suggested statistically insignificant trends toward improved LRFS. Additional study may further understanding of relationships between PET findings at these time points and outcome in rhabdomyosarcoma.

Prospective Study of 3′-Deoxy-3′-18F-Fluorothymidine PET for Early Interim Response Assessment in Advanced-Stage B-Cell Lymphoma

Current clinical and imaging tools remain suboptimal for early assessment of prognosis and treatment response in aggressive lymphomas. PET with 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) can be used to measure tumor cell proliferation and treatment response. In a prospective study in patients with advanced-stage B-cell lymphoma, we investigated the prognostic and predictive value of 18F-FLT PET in comparison to standard imaging with 18F-FDG PET and clinical outcome. Methods: Sixty-five patients were treated with an induction/consolidation regimen consisting of 4 cycles of R-CHOP-14 (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) followed by 3 cycles of ICE (ifosfamide, carboplatin, etoposide). 18F-FLT PET was performed at baseline and at interim (iPET) after 1–2 cycles of therapy. 18F-FDG PET was performed at baseline, after cycle 4, and at the end of therapy. The relationship between PET findings, progression-free survival (PFS) and overall survival (OS) was investigated. Results: With a median follow-up of 51 mo, PFS and OS were 71% and 86%, respectively. 18F-FLT iPET, analyzed visually (using a 5-point score) or semiquantitatively (using SUV and ΔSUV) predicted both PFS and OS (P < 0.01 for all parameters). Residual 18F-FLT SUVmax on iPET was associated with an inferior PFS (hazard ratio, 1.26, P = 0.001) and OS (hazard ratio, 1.27, P = 0.002). When 18F-FDG PET was used, findings in the end of treatment scan were better predictors of PFS and OS than findings on the interim scan. Baseline PET imaging parameters, including SUV, proliferative volume, or metabolic tumor volume, did not correlate with outcome. Conclusion: 18F-FLT PET after 1–2 cycles of chemotherapy predicts PFS and OS, and a negative 18F-FLT iPET result may potentially help design risk-adapted therapies in patients with aggressive lymphomas. In contrast, the positive predictive value of 18F-FLT iPET remains too low to justify changes in patient management.

Positron Emission Tomography/Computed Tomography–Based Assessments of Androgen Receptor Expression and Glycolytic Activity as a Prognostic Biomarker for Metastatic Castration-Resistant Prostate Cancer

Importance Androgen receptor–signaling inhibitor (ARSi) drugs prolong life in metastatic castration–resistant prostate cancer (mCRPC), but such tumors eventually become resistant and progress. Comprehensive positron emission tomography/computed tomography (PET/CT) imaging using fluoro-2-D-deoxyglucose F 18 ([18F]-FDG) for glycolysis (Glyc) and fluorodihydrotestosterone F 18 ([18F]-FDHT) for androgen receptor (AR) expression determine heterogeneity of imaging phenotypes, which may be useful in distinguishing patients who will benefit from ARSi drugs from those who need alternative treatments. Objective To test the hypothesis that PET/CT-based assessments of AR expression and glycolytic activity would reveal heterogeneity affecting prognosis. Design, Setting, and Participants Between April 6, 2007, and October 4, 2012, patients with mCRPC underwent imaging with both [18F]-FDG and [18F]-FDHT at Memorial Sloan Kettering Cancer Center. The patients were naive to ARSi treatment with enzalutamide or abiraterone acetate and were referred during documented disease progression. Image-directed biopsy determined the presence or absence of prostate cancer at positive imaging sites. Interventions PET/CT imaging was performed with [18F]-FDHT and [18F]-FDG; select individual lesions were biopsied to correlate imaging phenotype with histologic findings. Main Outcomes and Measures All metabolically active lesions were interpreted as [18F]-FDHT-positive (AR1) or [18F]-FDHT-negative (AR0) and as [18F]-FDG-positive (Glyc1) or [18F]-FDG-negative (Glyc0). Correlation was performed with overall survival for both individual lesion imaging phenotype as well as patient-specific imaging phenotype. Results The mean (SD) age of the 133 patients was 68 (8.6) years. Imaging phenotypes of 2405 PET/CT-positive lesions (median, 12.0 per patient) included 1713 (71.2%) AR1Glyc1, 386 (16.0%) AR1Glyc0, and 306 (12.7%) AR0Glyc1. On multivariate analysis, each phenotype had an independent negative impact effect on survival, most pronounced for AR0Glyc1 lesions (hazard ratio [HR], 1.11; 95% CI, 1.05-1.16; P < .001), followed by AR1Glyc1 lesions (HR, 1.05; 95% CI, 1.03-1.06; P < .001) and AR1Glyc0 lesions (HR, 1.03; 95% CI, 1.00-1.05; P = .048). When sorted by lesion type, 4 patient-specific groups emerged: (1) concordant, with all AR1Glyc1 (34 patients [25.6%]); (2) AR predominant, with AR1Glyc1 and varying numbers of AR1Glyc0 (33 [24.8%]); (3) Glyc predominant, with AR1Glyc1 and varying numbers of AR0Glyc1 (40 [30.1%]); and (4) mixed, with AR1Glyc1 plus a mixture of varying numbers of AR1Glyc0 and AR0Glyc1 (26 [19.5%]). Conclusions and Relevance Heterogeneity of PET/CT imaging phenotype has clinical relevance on a lesion and individual patient level. With regard to mCRPC lesions, most express ARs, consistent with initial benefit of ARSi drugs. On a patient basis, 49% (groups 3 and 4) had at least 1 AR0Glyc1 lesion—the imaging phenotype with the most negative effect on survival, possibly due to ARSi resistance.

Metabolic tumor volume and total lesion glycolysis on FDG-PET/CT can predict overall survival after 90Y radioembolization of colorectal liver metastases: A comparison with SUVmax, SUVpeak, and RECIST 1.0

PURPOSE To compare the performance of 4 metrics of metabolic response on FDG-PET/CT against RECIST 1.0 for determining response and predicting overall survival (OS) following (90)Y resin microspheres radioembolization of colorectal liver metastases (CLM). METHODS We conducted an IRB-waived retrospective review of our radioembolization database to identify patients with unresectable CLM treated between December 2009 and December 2013. We included patients who had both PET/CT and contrast enhanced CT (CECT) available at baseline and on the first follow-up post-radioembolization. On baseline CECT up to five target tumors were chosen per patient according to RECIST 1.0. Four metrics of FDG-avidity (SUVmax, SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG)) on PET/CT were measured for the same target tumors. Using RECIST 1.0, patients were classified as no progression (partial response or stable disease) and progression. For each PET metric, a cut-off point of ≥30% decrease was chosen to define response. OS was calculated from the time of radioembolization using Kaplan-Meier methodology. The log-rank test was used for univariate analysis to identify predictors of OS. RESULTS The study enrolled 49 patients with 119 target tumors; a median of 2 (range: 1-5) tumors were selected per patient. Median OS was 12.7 months (95%CI: 7.2-16.7). Response by MTV (P=0.035) and TLG (P=0.044) reached statistical significance in predicting OS. Response by SUVmax (P=0.21), SUVpeak (P=0.20) or no progression by RECIST 1.0 (P=0.44) did not predict OS. CONCLUSION Metabolic response based on changes in MTV and TLG can predict OS post-radioembolization of CLM.

Utility of FDG‐PET in clinical neuroendocrine prostate cancer

Fluorodeoxyglucose (FDG) positron emission tomography (PET) has well‐characterized limitations in prostate adenocarcinoma (PCA). However, data assessing the utility of PET in neuroendocrine prostate cancer (NEPC) is limited to isolated case reports. Herein, we describe the first case series to assess the utility of FDG‐PET in NEPC.

Utility of 18F-FDG–PET/CT in Soft Tissue Sarcomas

Rhabdomyosarcoma (RMS), together with synovial sarcoma, is the most common soft tissue sarcoma in children and adolescents. These tumors can arise anywhere in the body. 18F-FDG–PET/CT provides important additional information in the initial staging of RMS, with a significant impact on its therapeutic management. This imaging approach is also of high prognostic value in the early assessment of the therapeutic response.

Poorly Differentiated Thyroid Carcinoma

Poorly differentiated thyroid cancers are very rare. Due to its aggressive growth and subsequent significantly elevated glucose utilization, several case reports have shown FDG-PET/CT’s ability to detect both primary and metastatic anaplastic thyroid cancer