Maria Liza Lindenberg

11C-Acetate PET/CT in Localized Prostate Cancer: A Study with MRI and Histopathologic Correlation

This work characterizes the uptake of 11C-acetate in prostate cancer (PCa), benign prostate hyperplasia, and normal prostate tissue in comparison with multiparametric MRI, whole-mount histopathology, and clinical markers to evaluate the potential utility of 11C-acetate for delineating intraprostatic tumors in a population of patients with localized PCa. Methods: Thirty-nine men with presumed localized PCa underwent dynamic–static abdominal–pelvic 11C-acetate PET/CT for 30 min and 3-T multiparametric MRI before prostatectomy. PET/CT images were registered to MR images using pelvic bones for initial rotation–translation, followed by manual adjustments to account for prostate motion and deformation from the MRI endorectal coil. Whole-mount pathology specimens were sectioned using an MRI-based patient-specific mold resulting in improved registration between the MRI, PET, and pathology. 11C-acetate PET standardized uptake values were compared with multiparametric MRI and pathology. Results: 11C-acetate uptake was rapid but reversible, peaking at 3–5 min after injection and reaching a relative plateau at approximately 10 min. The average maximum standardized uptake value (10–12 min) of tumors was significantly higher than that of normal prostate tissue (4.4 ± 2.05 [range, 1.8–9.2] vs. 2.1 ± 0.94 [range, 0.7–3.4], respectively; P < 0.001); however, it was not significantly different from that of benign prostatic hyperplasia (4.8 ± 2.01 [range, 1.8–8.8]). A sector-based comparison with histopathology, including all tumors greater than 0.5 cm, revealed a sensitivity and specificity of 61.6% and 80.0%, respectively, for 11C-acetate PET/CT and 82.3% and 95.1%, respectively, for MRI. The 11C-acetate accuracy was comparable to that of MRI when only tumors greater than 0.9 cm were considered. In a small cohort (n = 9), 11C-acetate uptake was independent of fatty acid synthase expression using immunohistochemistry. Conclusion: 11C-acetate PET/CT demonstrates higher uptake in tumor foci than in normal prostate tissue; however, 11C-acetate uptake in tumors is similar to that in benign prostate hyperplasia nodules. Although 11C-acetate PET/CT is not likely to have utility as an independent modality for evaluation of localized PCa, the high uptake in tumors may make it useful for monitoring focal therapy when tissue damage after therapy may limit anatomic imaging methods.

Review of functional/anatomical imaging in oncology.

Patient management in oncology increasingly relies on imaging for diagnosis, response assessment, and follow-up. The clinical availability of combined functional/anatomical imaging modalities, which integrate the benefits of visualizing tumor biology with those of high-resolution structural imaging, revolutionized clinical management of oncologic patients. Conventional high-resolution anatomical imaging modalities such as computed tomography (CT) and MRI excel at providing details on lesion location, size, morphology, and structural changes to adjacent tissues; however, these modalities provide little insight into tumor physiology. With the increasing focus on molecularly targeted therapies, imaging radiolabeled compounds with PET and single-photon emission tomography (SPECT) is often carried out to provide insight into a tumor’s biological functions and its surrounding microenvironment. Despite their high sensitivity and specificity, PET and SPECT alone are substantially limited by low spatial resolution and inability to provide anatomical detail. Integrating SPECT or PET with a modality capable of providing these (i.e. CT or MR) maximizes their separate strengths and provides anatomical localization of physiological processes with detailed visualization of a tumor’s structure. The availability of multimodality (hybrid) imaging with PET/CT, SPECT/CT, and PET/MR improves our ability to characterize lesions and affect treatment decisions and patient management. We have just begun to exploit the truly synergistic capabilities of multimodality imaging. Continued advances in the development of instrumentation and imaging agents will improve our ability to noninvasively characterize disease processes. This review will discuss the evolution of hybrid imaging technology and provide examples of its current and potential future clinical uses.

Localized Prostate Cancer Detection with 18F FACBC PET/CT: Comparison with MR Imaging and Histopathologic Analysis

PURPOSE To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid ((18)F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging. MATERIALS AND METHODS Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study. Twenty-one men underwent dynamic and static abdominopelvic (18)F FACBC combined positron emission tomography (PET) and computed tomography (CT) and multiparametric (MP) 3-T endorectal MR imaging before robotic-assisted prostatectomy. PET/CT and MR images were coregistered by using pelvic bones as fiducial markers; this was followed by manual adjustments. Whole-mount histopathologic specimens were sliced with an MR-based patient-specific mold. (18)F FACBC PET standardized uptake values (SUVs) were compared with those at MR imaging and histopathologic analysis for lesion- and sector-based (20 sectors per patient) analysis. Positive and negative predictive values for each modality were estimated by using generalized estimating equations with logit link function and working independence correlation structure. RESULTS (18)F FACBC tumor uptake was rapid but reversible. It peaked 3.6 minutes after injection and reached a relative plateau at 15-20 minutes (SUVmax[15-20min]). Mean prostate tumor SUVmax(15-20min) was significantly higher than that of the normal prostate (4.5 ± 0.5 vs 2.7 ± 0.5) (P < .001); however, it was not significantly different from that of BPH (4.3 ± 0.6) (P = .27). Sector-based comparison with histopathologic analysis, including all tumors, revealed sensitivity and specificity of 67% and 66%, respectively, for (18)F FACBC PET/CT and 73% and 79%, respectively, for T2-weighted MR imaging. (18)F FACBC PET/CT and MP MR imaging were used to localize dominant tumors (sensitivity of 90% for both). Combined (18)F FACBC and MR imaging yielded positive predictive value of 82% for tumor localization, which was higher than that with either modality alone (P < .001). CONCLUSION (18)F FACBC PET/CT shows higher uptake in intraprostatic tumor foci than in normal prostate tissue; however, (18)F FACBC uptake in tumors is similar to that in BPH nodules. Thus, it is not specific for prostate cancer. Nevertheless, combined (18)F FACBC PET/CT and T2-weighted MR imaging enable more accurate localization of prostate cancer lesions than either modality alone.

Functional and molecular imaging of localized and recurrent prostate cancer

Prostate cancer is the most common malignancy among American men. Imaging of localized and recurrent prostate cancer is challenging since conventional imaging techniques are limited. New imaging techniques such as multiparametric MRI and PET with targeted tracers have been investigated extensively in the last decade. As a result, the role of novel imaging techniques for the detection of localized and recurrent prostate cancer has recently expanded. In this review, novel functional and molecular imaging techniques used in the management of localized and recurrent prostate cancer are discussed.

A Phase II Study of Sorafenib Combined With Cetuximab in EGFR-Expressing, KRAS-Mutated Metastatic Colorectal Cancer

BACKGROUND Mutations in the KRAS gene predict for resistance to anti-epidermal growth factor receptor (EGFR) therapies, including cetuximab. Upregulation of vascular endothelial growth factor (VEGF)-A has been implicated in resistance to anti-EGFR treatment. Abrogation of the VEGF and RAS/RAF/MEK/ERK pathways has the potential to restore cetuximab sensitivity. PATIENTS AND METHODS Adult patients with histologically documented, measurable, EGFR-expressing, KRAS-mutated metastatic colorectal cancer (mCRC) that had progressed after 5-fluorouracil-based regimens were treated with sorafenib 400 mg orally twice daily and intravenous cetuximab weekly in 28-day cycles. The primary endpoint was the response rate (complete response, partial response, and stable disease at 4 cycles). The secondary endpoints included plasma biomarker analysis of angiogenic cytokines and correlative imaging studies with dynamic contrast-enhanced magnetic resonance imaging and zirconium 89-panitumumab. RESULTS Of the 30 patients enrolled, 26 were evaluable for response. Of the 26 patients evaluated, 4 had stable disease at 4 cycles and 1 had stable disease at 8 cycles. The median progression-free survival was 1.84 months. The common toxicities were rash, diarrhea, and liver enzyme elevations. Of the angiogenic cytokines evaluated, only the placental growth factor increased significantly with treatment (P < .0001). No pharmacodynamic parameters were associated with the treatment response. CONCLUSION We report the results of a trial that combined cetuximab and sorafenib for the treatment of KRAS-mutated mCRC, with correlative imaging studies and pharmacodynamic angiogenic cytokine profiling as downstream markers of EGFR and VEGF receptor (VEGFR) signaling. No objective responses were observed. Additional development of biomarkers for patient selection is needed to evaluate combined EGFR and VEGFR blockade as a therapeutic option in KRAS-mutated CRC.

Imaging Locally Advanced, Recurrent, and Metastatic Prostate Cancer: A Review

Importance Prostate cancer is the second leading cause of cancer deaths in US men. The course of prostate cancer is highly variable, and timely and accurate detection of clinically significant cancer is critical in positively affecting outcomes. Observations Molecular imaging methods and magnetic resonance imaging (MRI) are the most promising new developments for prostate tumor visualization. While the benefits of MRI are many, positron emission tomography (PET) radiotracers are still available only as research tools. Conclusions and Relevance The current research-based evidence on PET imaging has demonstrated encouraging potential in the initial diagnosis and detection of recurrence and metastases of prostate cancer.

A pilot study of the value of 18F-fluoro-deoxy-thymidine PET/CT in predicting viable lymphoma in residual 18F-FDG avid masses after completion of therapy.

Background Despite its success in diagnosing and staging lymphoma, 18F-FDG PET/CT can be falsely positive in areas of posttreatment inflammation. 3′-18F-fluoro-3′-deoxy-l-thymidine (18F-FLT) is a structural analog of the DNA constituent thymidine; its uptake correlates with cellular proliferation. This pilot study evaluates the ability of 18F-FLT PET/CT to distinguish viable lymphoma from posttreatment inflammatory changes in 18F-FDG avid residual masses. Methods Twenty-one patients with lymphoma with at least 1 18F-FDG avid residual mass after therapy underwent 18F-FLT PET/CT imaging. 18F-FDG and 18F-FLT uptake values were compared, including quantitative pharmacokinetic parameters extracted from the 18F-FLT time activity curves generated from dynamic data using graphical and nonlinear compartmental modeling. Results The true nature of the residual mass was confirmed by biopsy in 12 patients (8 positive and 4 negative for viable lymphoma and by follow-up CT and/or repeat 18F-FDG PET/CT imaging over 1 year); among the remaining 9 patients, 7 lesions resolved or decreased and 2 showed growth indicative of lymphoma. 18F-FLT PET SUVest.max was significantly higher in tumors than in benign lesions (5.5 [2.2] vs 1.7 [0.6]; P < 0.0001), whereas the difference in 18F-FDG SUVs was not significant (malignant, 7.8 [3.8] vs benign, 5.4 [2.4]; P = 0.11). All of the benign lesions had an 18F-FLT SUVest.max of less than 3.0. Conclusions 18F-FLT shows improved specificity over 18F-FDG in distinguishing residual lymphoma from posttreatment inflammation and may be useful in the evaluation of patients with residual 18F-FDG–positive masses after completing therapy.

Positron emission tomography (PET) in primary prostate cancer staging and risk assessment

Prostate cancer (PCa) is one of the few neoplasms that are not well served by 18F-Fluorodeoxyglucose (FDG) positron emission tomography (PET). As a result, a number of PET tracers have been developed to target particular biological features of PCa. Such agents can be used for diagnosis, staging, identification of biochemical recurrence (BCR) and evaluation of metastatic disease. Here, we focus on primary disease and local staging. To date, magnetic resonance imaging (MRI) has proven superior to PET in the imaging of primary PCa. However, some PET agents have shown remarkable promise in staging high-risk PCa (defined as any combination of a clinical T3, a PSA score >20 ng/mL, or a Gleason score of 8–10), as well as biochemical relapse after definitive therapy and metastatic PCa. PET agents can be divided into those that interrogate tumor metabolism (18F-FDG, 11C-Choline, 18F-Choline, 11C-Acetate, 18F-FACBC), hormone receptors (18F-FDHT), and other targets such as prostate specific membrane antigen (PSMA) (68Ga-PSMA, 18F-DCFBC, 18F-DCFPyl) or gastric releasing peptide (18F-GRP or 18F-Bombesin). In this review, we compare the available PCa targeted PET tracers utilized in staging of high risk tumors.

Meeting the challenges of PET-based molecular imaging in cancer

As personalized medicine becomes a reality, there is a need for specific imaging agents that reflect molecular characteristics of a cancer. Fluorodeoxyglucose is an important advance because of its sensitivity. Newer molecular imaging probes offer higher specificity and are categorized as: radiolabeled biomimetics; antibody–antibody fragments and drug–drug-like compounds. Biomimetics have high sensitivity but tend to be less specific as they often engage natural transporters and metabolic pathways. Antibodies and their fragments are specific but may be limited by slow clearance. Labeled drugs and drug-like compounds offer good specificity but may be limited in sensitivity. There are numerous challenges facing molecular imaging related to their complexity. Additionally, fear of ionizing radiation and regulatory constraints have somewhat inhibited clinical translation. However, there is reason for optimism due to economies of scale and a changing health care system, which places a premium on diagnostic accuracy. Although molecular imaging is not likely to become mainstream in the near future, its long-term prospects for doing so are excellent.

Abstract B43: ANG1005, a novel brain-penetrant drug conjugate, in CNS metastases from breast cancer: FLT-PET imaging as a predictor of response

Background: The novel drug conjugate ANG1005 consists of 3 molecules of paclitaxel covalently linked to Angiopep-2. After binding to the low-density lipoprotein receptor-related protein, ANG1005 crosses the blood brain barrier (BBB) by endocytosis. A multi-center Phase II study, with the primary endpoint of intracranial response in patients with breast cancer brain metastases is in progress. At the NCI, a biomarker substudy is evaluating 18F-FLT (39-Fluoro-39 deoxythymidine)-PET for response assessment. Methods: Patients with measurable brain metastases from breast cancer received ANG1005 at a dose of 550mg/m2 IV once every 21 days. Before and after cycle 1, all patients on study underwent imaging with 18F-FLT, a thymidine analog and novel imaging agent; retention of 18F-FLT correlating with DNA synthesis. In order to detect brain metastases and assess response to treatment, we compared FLT PET images with MRI-gadolinium contrast scans, obtaining both dynamic and static images. We determined the percentage (%) change after treatment with ANG1005; a decrease in ≥20% was considered significant. Results: Ten patients were enrolled on study. A total of 32 target and 20 non target CNS lesions in 10 patients were imaged and analyzed by MRI and FLT-PET. At 30 minutes, SUVmax ranged from 0.8 to 6.3 at baseline (mean 2.64), and the SUV80%, (mean of top 20% SUV units) ranged from 0.7 to 5.12. The median% change from baseline to post one cycle of ANG1005 was -19.9% for SUVmax (range +85.4 to -67.7, and was median -20.2% for SUV80% (range 95.7 to -69%). Two patients had confirmed partial responses lasting 6 and 18 cycles, respectively. Six patients had stable disease and received a median of 6 cycles. Tumor reductions, as determined by MRI per CNS RECIST version 1.1 ranged from -5% to -60% in lesion size, compared to baseline. Both FLT-PET parameters correlated with the% change in MRI measurements in the target lesions (R2 = 0.64, P = 0.0002). Conclusion: The development of CNS-directed therapies designed to cross the BBB, such as the paclitaxel conjugate ANG1005, is a research priority. As contrast-enhanced MRI detection of brain metastases is representative of gadolinium leakage through the BBB, as opposed to actual tumor volume, better approaches are needed to evaluate drug efficacy. Pilot evaluations of FLT-PET imaging in this setting suggest that it is a promising tool that may serve as a complementary assessment method for breast cancer brain metastases going forward. Citation Format: Ciara C. O9Sullivan, Maria Lindenberg, Christine Bryla, Nicole Davarpanah, Cody Peer, Nicholas Patronas, Laleh Amiri-Kordestani, Sanjeeve Balasubramaniam, Tito Fojo, William D. Figg, Peter Choyke. ANG1005, a novel brain-penetrant drug conjugate, in CNS metastases from breast cancer: FLT-PET imaging as a predictor of response. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B43.