Sandi A. Kwee

Combined Use of F‐18 Fluorocholine Positron Emission Tomography and Magnetic Resonance Spectroscopy for Brain Tumor Evaluation

Background. Choline metabolism is often abnormal in malignant brain tumors.Methods. Brain positron emission tomography (PET) imaging with F‐18 fluorocholine (FCH) was performed on 2 patients with intracranial lesions suspected to be high‐grade malignant gliomas on the basis of magnetic resonance (MR) imaging and multivoxel 1H‐MR spectroscopic imaging (MRSI) findings. Standardized uptake value (SUV) measurements on PET were compared with measurements of choline/creatine metabolite ratio on MRSI in corresponding regions. Brain biopsy revealed glioblastoma multiforme (GBM) in one case and demyelinating disease in the other.Results. In the case of GBM, the tumor demonstrated increased FCH uptake on PET. The mean and maximum SUV in areas of the tumor correlated with regional choline/ creatine ratio measurements (r= 0.76,P < .001;r= 0.83,P < .001, respectively). In the case of tumefactive demyelinating lesions, the lesion demonstrated low FCH uptake, which did not correlate with choline/ creatine ratio measurements.Conclusions. Assessments of choline metabolism may aid in evaluating intracranial mass lesions.

Use of step-section histopathology to evaluate 18F-fluorocholine PET sextant localization of prostate cancer.

To assess positron emission tomography (PET) with fluorine-18 fluorocholine for sextant localization of malignant prostate tumors. Histopathologic analysis was performed on step-sectioned whole-mounted prostate specimens from 15 patients who underwent PET with fluorocholine prior to radical prostatectomy. The maximum standardized uptake value (SUVmax) corresponding to prostate sextants on PET was measured by region of interest analysis and compared with histopathologic results. Histopathology demonstrated malignant involvement in 61 of 90 prostate sextants. The mean total tumor volume per specimen was 4.9 mL (range 0.01–28.7 mL). Mean SUVmax was 6.0 ± 2.0 in malignant sextants and 3.8 ± 1.4 in benign sextants (p < .0001). The area under the receiver operating characteristic curve was 0.82 for sextant detection of malignancy based on SUVmax measurement. Tumor diameter directly correlated with sextant SUVmax in malignant sextants (r = .54, p < .05). In 13 subjects, the largest tumor in the specimen corresponded to the sextant with the highest SUVmax. Fluorocholine PET can serve to localize dominant areas of malignancy in patients with prostate cancer. However, PET with fluorocholine may fail to identify sextants with smaller volumes of malignancy.

Prognosis Related to Metastatic Burden Measured by ¹⁸F-Fluorocholine PET/CT in Castration-Resistant Prostate Cancer.

This study investigated the prognostic significance of metabolically active tumor volume (MATV) measurements applied to 18F-fluorocholine PET/CT in castration-resistant prostate cancer (CRPC). Methods: 18F-fluorocholine PET/CT imaging was performed on 30 patients with CRPC. Metastatic disease was quantified on the basis of maximum standardized uptake value (SUVmax), MATV, and total lesion activity (TLA = MATV × mean standardized uptake value). Tumor burden indices derived from whole-body summation of PET tumor volume measurements (i.e., net MATV and net TLA) were evaluated as variables in Cox regression and Kaplan–Meier survival analyses. Results: Net MATV ranged from 0.12 cm3 to 1,543.9 cm3 (median, 52.6 cm3). Net TLA ranged from 0.40 to 6,688.7 g (median, 225.1 g). Prostate-specific antigen level at the time of PET correlated significantly with net MATV (Pearson r = 0.65, P = 0.0001) and net TLA (r = 0.60, P = 0.0005) but not highest lesional SUVmax of each scan. Survivors were followed for a median 23 mo (range, 6–38 mo). On Cox regression analyses, overall survival had a significant association with net MATV (P = 0.0068), net TLA (P = 0.0072), and highest lesion SUVmax (P = 0.0173) and a borderline association with prostate-specific antigen level (P = 0.0458). Only net MATV and net TLA remained significant in univariate-adjusted survival analyses. Kaplan–Meier analysis demonstrated significant differences in survival between groups stratified by median net MATV (log-rank P = 0.0371), net TLA (log-rank P = 0.0371), and highest lesion SUVmax (log-rank P = 0.0223). Conclusion: Metastatic prostate cancer detected by 18F-fluorocholine PET/CT can be quantified on the basis of volumetric measurements of tumor metabolic activity. The prognostic value of 18F-fluorocholine PET/CT may stem from this capacity to assess whole-body tumor burden. With further clinical validation, 18F-fluorocholine PET-based indices of global disease activity and mortality risk could prove useful in patient-individualized treatment of CRPC.

Detection of synchronous primary breast and prostate cancer by F-18 fluorocholine PET/CT.

Abstract:There is growing experience with F-18 fluorocholine (FCH) for positron emission tomography/computed tomography (PET/CT) imaging of prostate cancer, but limited experience in breast cancer. We report the PET detection of synchronous cancers of the breast and prostate. A 68-year-old man with

Prediction of PSA Progression in Castration-Resistant Prostate Cancer Based on Treatment-Associated Change in Tumor Burden Quantified by 18F-Fluorocholine PET/CT

Measurements of metabolically active tumor volume (MATV) can be applied to 18F-fluorocholine PET/CT to quantify whole-body tumor burden. This study evaluated the serial application of these measurements as systemic treatment response markers and predictors of disease progression in patients with castration-resistant prostate cancer (CRPC). Methods: Forty-two patients completed sequential 18F-fluorocholine PET/CT scans before and 1–3 mo after starting treatment for CRPC. Whole-body tumor segmentation was applied to determine net MATV from each scan. Changes in net MATV were evaluated as predictors of time to prostate-specific antigen (PSA) progression by Kaplan–Meier and proportional hazards regression analysis. Results: Treatments consisted of chemotherapy in 16 patients, antiandrogens in 19 patients, 223Ra-dichloride in 5 patients, and sipuleucel-T in 2 patients. A significant MATV response (defined as a ≥30% decrease in net MATV) was observed in 20 patients on the basis of in-treatment PET/CT performed an average of 51 d (median, 49 d) into treatment. Significantly longer times to PSA progression were observed in patients who exhibited an MATV response (418 d vs. 116 d, P = 0.0067). MATV response was associated with a hazard ratio of 0.246 (P = 0.0113) for PSA progression, which remained significant when adjusted for treatment type. Conclusion: Significant changes in whole-body tumor burden can be measured on 18F-fluorocholine PET/CT over the course of contemporary treatments for CRPC. In this study, these changes were found to be predictive of PSA progression as a potential surrogate marker of treatment outcome. Because 18F-fluorocholine PET/CT can also be used for localizing resistant tumors, this modality can potentially complement other measures of response in the precision management of advanced prostate cancer.

The Impact of Urinary Excretion of 18F-Labeled Choline Analogs

TO THE EDITOR: We have read with interest the article of Schuster et al. (1) on the initial evaluation of an 18F-labeled amino acid transport tracer, anti-1-amino-3-18F-fluorocyclobutyl-1carboxylic acid (FACBC) in patients with prostate cancer. In this preliminary study on a small cohort of patients, FACBC appeared to have several favorable properties for the imaging of prostate cancer in the pelvic region, including avid uptake in primary tumors and metastases in lymph nodes and bone, relatively lower uptake in nonmalignant tissues of the prostate or lymph nodes, and low urinary excretion. The results showed a certain promise that the evaluation of amino acid transport function with this tracer may be useful in new and recurrent prostate cancer. However, we would like to respond to the comments of the authors that imaging of prostate cancer with 18F-labeled choline (FCH) is disadvantaged because of its relatively higher urinary excretion pattern. The urinary excretion of FCH has been reported to be 4.9% 6 4.8% of the administered dose in female patients and 1.9% 6 1.6% in male patients within the first hour after injection (2). Because of the extremely rapid renal clearance of FCH, most of the urinary radioactivity generally arrives at the urinary bladder within the first 20 min. Although urinary activity has the potential to confound the imaging of prostate cancer, image acquisition protocols have been designed to minimize the impact of this potential problem. Dynamic imaging over the pelvic region for the first 10 min after injection allows clear delineation of tumor uptake that precedes the appearance of radioactivity in the ureters and bladder (3,4). Consequently, it is possible to retrospectively exclude frames that show significant urinary interference. Furthermore, because there is rapid circulatory and urinary clearance of tracer but little washout from malignant tumors, voiding followed by delayed scanning with or without gentle hydration can also lead to satisfactory prostate images with high tumor-to-background contrast (5). The dynamic imaging information is useful not only for exclusion of urinary radioactivity but also for understanding the relationship of early FCH uptake, indicative of tracer delivery (perfusion) and choline transport, and of later tissue retention that is dependent on intracellular metabolism. In this regard, Schuster et al. (1) also found dynamic imaging to provide important information on FACBC kinetics: The amino acid analog was found to be transported but not metabolically trapped. Thus, the relative advantage of the lower urinary excretion of FACBC diminishes as the tracer washes out of malignant regions. The use of FACBC for whole-body imaging may require short image acquisition protocols, which may limit detection sensitivity for tumors. It will be of high interest to understand how rates of amino acid transport in prostate cancer, as seen with FACBC, relate to rates of choline transport and choline kinase activity, as seen with positron-labeled choline analogs.

Soft Tissue Response on 18F-Fluorocholine PET/CT in Metastatic Castrate-Resistant Prostate Cancer Treated With 223Ra-Dichloride: A Possible Abscopal Effect?

Two patients with castrate-resistant prostate cancer and symptomatic skeletal metastases underwent F-fluorocholine PET/CT prior to treatment with Ra-dichloride to reveal additional active lesions in the prostate gland and lymph nodes. Subsequent scans performed at the midpoint and end of Ra-dichloride therapy showed resolution of this soft tissue activity alongside declining bone lesion activity. Concomitant increases in plasma interleukin 6 were detected, suggesting that immune system activation may have mediated the soft tissue response. Abscopal effects usually encountered with external beam radiotherapy may also be occurring with Ra-dichloride therapy.

Metabolic positron emission tomography imaging of cancer: Pairing lipid metabolism with glycolysis.

The limitations of fluorine-18 fluorodeoxy-D-glucose (FDG) in detecting some cancers has prompted a longstanding search for other positron emission tomography (PET) tracers to complement the imaging of glycolysis in oncology, with much attention paid to lipogenesis based on observations that the production of various lipid and lipid-containing compounds is increased in most cancers. Radiolabeled analogs of choline and acetate have now been used as oncologic PET probes for over a decade, showing convincingly improved detection sensitivity over FDG for certain cancers. However, neither choline nor acetate have been thoroughly validated as lipogenic biomarkers, and while acetyl-CoA produced from acetate is used in de-novo lipogenesis to synthesize fatty acids, acetate is also consumed by various other synthetic and metabolic pathways, with recent experimental observations challenging the assumption that lipogenesis is its predominant role in all cancers. Since tumors detected by acetate PET are also frequently detected by choline PET, imaging of choline metabolism might serve as an alternative albeit indirect marker of lipogenesis, particularly if the fatty acids produced in cancer cells are mainly destined for membrane synthesis through incorporation into phosphatidylcholines. Aerobic glycolysis may or may not coincide with changes in lipid metabolism, resulting in combinatorial metabolic phenotypes that may have different prognostic or therapeutic implications. Consequently, PET imaging using dual metabolic tracers, in addition to being diagnostically superior to imaging with individual tracers, could eventually play a greater role in supporting precision medicine, as efforts to develop small-molecule metabolic pathway inhibitors are coming to fruition. To prepare for this advent, clinical and translational studies of metabolic PET tracers must go beyond simply estimating tracer diagnostic utility, and aim to uncover potential therapeutic avenues associated with these metabolic alterations.