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Originally published as JCO Early Release 10.1200/JCO.2005.03.5279 on April 24 2006 © 2006 American Society of Clinical Oncology. 11C-Acetate Positron Emission Tomography Imaging and Image Fusion With Computed Tomography and Magnetic Resonance Imaging in Patients With Recurrent Prostate Cancer
From the Departments of Nuclear Medicine, Radiotherapy, and Urology and Clinical Division of Oncology, Department of Medicine I, Hospital Pharmacy of the General Hospital of Vienna, Medical University of Vienna, Vienna, Austria Address reprint requests to Stefan Wachter, MD, Medical School Vienna, Department of Radiotherapy, Währinger Gürtel 18-20, 1090 Vienna, Austria; e-mail: wachter{at}ef1.at
PURPOSE: To assess the clinical value of computed tomography (CT) and magnetic resonance imaging (MRI) image fusion with 11C-acetate (AC) positron emission tomography (PET) imaging for detection and exact location of clinically occult recurrences. PATIENTS AND METHODS: Fifty prostate cancer patients with elevated/increasing serum prostate-specific antigen levels after radical therapy underwent whole-body AC PET. Uptake was initially interpreted as normal, abnormal, or equivocal. In case of abnormal or equivocal uptake, additional conventional imaging techniques, such as CT, MRI, and bone scans, were performed. To precisely define the anatomic location of abnormal uptake and to improve characterization of equivocal lesions, a software-assisted image fusion (CT-PET, MRI-PET) was performed and evaluated as site-by-site analysis of 51 abnormal (n = 37) or equivocal (n = 14) sites of all 50 patients. In 17 patients, additional histopathologic evaluation was available. RESULTS: In five (10%), 13 (26%), and 32 (64%) of the 50 patients, AC PET studies demonstrated AC uptake judged as normal, equivocal, and abnormal, respectively. Image fusion changed characterization of equivocal lesions as normal in five (10%) of 51 sites and abnormal in nine (18%) of 51 sites. It precisely defined the anatomic location of abnormal uptake in 37 (73%) of 51 sites. AC PET findings did influence patient management in 14 (28%) of 50 patients. CONCLUSION: Retrospective fusion of AC PET and CT/MRI is feasible and seems to be essential for final diagnosis. This is particularly true in patients with AC uptake in the prostate region.
Regardless of the established primary treatment for prostate cancer, a substantial portion of patients will experience relapse, heralded by detectable or increasing serum prostate-specific antigen (PSA), which provides the earliest evidence of residual or recurrent disease.1-6 Treatment decisions subsequent to documented biochemical relapse rely critically on distinguishing between locoregional relapse in the prostatic bed and adjacent tissues, locoregional relapse in lymph nodes, and distant systemic failure. Although applied successfully in most malignant diseases, 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) shows a poor performance in prostate cancer.7-17 Over the past years, novel PET tracers have been introduced that may potentially balance the encountered weak points in prostate cancer staging. Apart from 11C- and 18F-choline, 11C-acetate (AC) seems to be highly promising. Shreve et al18 and Shreve and Gross19 were the first to report on the high uptake of AC in renal cell carcinoma and the tracer's potential to clearly differentiate between malignant and benign tissues. In the meantime, various working groups have tested the potential of AC PET imaging in prostate cancer diagnosis12,20-25 and provided encouraging results. AC showed a marked uptake in prostate cancer and was clearly more sensitive in detecting prostate cancer than [18F]FDG PET. Recently, it has been shown that the combined use of morphologic and metabolic imaging may be essential in oncology.26,27 It has been advocated that the hybrid PET/computed tomography (CT) scanner would provide improved diagnostic accuracy in locating malignant lesions. Alternatively, the retrospective coregistration of both anatomic and functional modalities can be used, although with limitations.28 However, this technique allows the combining of PET and magnetic resonance imaging (MRI), which may be essential in some patients. In this study, we investigated the clinical value of CT/MRI image fusion with AC imaging in patients with clinically occult recurrent prostate cancer.
Patients After having obtained written informed consent, 50 male patients with histologically proven adenocarcinoma of the prostate and increasing levels of PSA after primary treatment (radical prostatectomy or radiotherapy) were studied by AC PET and subsequent radiologic/nuclear medicine studies between January 2001 and July 2003.
AC PET AC was produced from carbon dioxide by Grignard's reaction. In short, no carrier–added [11C]CO2 was produced by a cyclone 18/9 cyclotron (IBA, Louvain-la-Neuve, Belgium) and trapped in a solution of methylmagnesium bromide 0.3 mol in tetrahydrofuran. The reaction solution was quenched with H2O 150 µL and evaporated to dryness under He purge at 120°C. Thereafter, 17% H3PO4 was added, and AC was distilled at 150°C with the aid of He purge and successive additions of H2O in a vial containing phosphate-buffered saline. After complete distillation, the resulting solution was sterile filtered and ready for medical use. The radiochemical yield was approximately 9 GBq for each run (56%), and the specific activity was approximately 7.4 GBq/µmol. AC PET scans were obtained with a dedicated PET system (GE Advance; General Electric, Milwaukee, WI) covering an axial field of view of 15.2 cm. For the attenuation correction, all patients underwent transmission scan. A standard pin source of 68 Ge was used for attenuation corrections of the emission images. The initial 15 patients were asked to void before scanning; the remaining patients were scanned with a full bladder. In all patients, whole-body emission scans were acquired (four bed positions, 5 minutes per bed position) from the mid thighs to the head at approximately 15 minutes after injection. A 740-MBq dose of AC was administered through the cubital vein over 10 seconds. Static images covering the prostate gland were obtained by scanning at 10 to 20 minutes after injection. Static emission scans were started 5 minutes after injection (5 minutes of acquisition time for one bed position). Attenuation-corrected scan data were reconstructed as filtered back-projection using a Hanning filter with a cutoff of 12 and iterative algorithms and reformatted in coronal, transaxial, and sagittal planes. The scans were interpreted independently by two nuclear medicine physicians. Interpretation criteria included the localization, shape, and intensity of the increased uptake.
CT
MRI
Image Fusion Morphologic (CT and MRI) and metabolic (PET) images were stored in a common database and visualized and reconstructed in any arbitrary plane by an in-house–developed software tool.30 Image fusion was performed as a synergistic exploitation of the coregistered studies after rigid body transformation (translation and rotation to achieve a high degree of similarity between the floating and the reference study). The whole procedure lasted at least 5 minutes and for an average of 9 minutes (range, 5 to 14 minutes).
Data Analysis Either on the same day as PET scanning or within few days thereafter, patients underwent correlative imaging studies. In case of abnormal or equivocal tracer uptake, a CT scan of the suspected region was performed. In case of a suspected local recurrence and/or locoregional pelvic lymph node involvement, an additional correlative MRI study of the region was performed. If indicated, a bone scan was also performed. Final evaluation of AC PET scans was performed after three-dimensional image fusion/correlation with conventional imaging by one experienced clinical radiologist. Results after image fusion were evaluated as site-by-site analysis of all abnormal or equivocal sites. After fusion of AC PET and CT/MRI, lymph nodes showing a focally increased uptake were considered malignant, even if they did not fulfill the established radiologic criteria of malignancy (ie, size, configuration, and contrast media uptake). In case of abnormal or equivocal AC PET uptake, histopathologic evaluation was requested but not recommended.
Patient Population The study population consisted of 50 asymptomatic prostate cancer patients (mean age, 66 years; range, 50 to 87 years) who had been treated with radical prostatectomy (n = 34), external-beam therapy (n = 12), or seed implantation (n = 4) as primary therapy and showed elevated/increasing PSA. At the time of AC PET scanning, the mean PSA level for the postprostatectomy group was 6.3 ng/mL (range, 0.5 to 24.9 ng/mL). In patients treated with external-beam radiation or seed implantation, the mean PSA level was 12.4 ng/mL (range, 1.15 to 23.7 ng/mL) and 9.9 ng/mL (range, 4.4 to 23.7 ng/mL), respectively. Patient characteristics, PET findings, and outcomes of CT/MRI image fusion are listed in Tables 1, 2, and 3.
Outcomes of AC PET Scanning and Results of Image Fusion Negative AC PET findings. In five (10%) of 50 patients, a normal AC accumulation was observed, which was characterized by a physiologic distribution of AC uptake in the upper abdominal parenchymatous organs (liver, spleen, and pancreas) and by minor uptake in muscles, intestines, and renal parenchymes. The median PSA level in these patients was 0.9 ng/mL (range, 0.5 to 13 ng/mL). Positive AC PET findings in prostate/prostatic bed. Considering AC PET scans only, a focally increased tracer uptake in the lower pelvis indicating local relapse was observed in 11 (22%) of 50 PET scans. In these patients, abnormal uptake was confirmed by MRI image fusion. Equivocal lesions were detected in 12 (24%) of 50 PET studies. After image fusion, four (33%) of 12 equivocal lesions were judged as definitely benign as a result of a tracer accumulation in direct projection to the urinary bladder. In the remaining eight (67%) of 12 lesions, tracer uptake could be correlated to the prostate or to a suspicious soft tissue mass within the prostatic bed. In four patients, the local recurrence/residual disease determined by AC PET and image fusion was additionally verified by biopsy (Table 4). In one patient, a negative biopsy was found, although the AC PET scan was judged malignant after image fusion. In another patient, a positive biopsy was found, although the AC PET scan was negative. In three patients, a negative AC PET scan was confirmed by a negative biopsy.
Positive AC PET findings in lymph nodes. Evaluating PET scans only, tracer uptake considered as malignant lymph nodes was observed in 13 patients. In one patient, previously considered equivocal findings as a result of potential physiologic uptake in the GI tract were characterized as definitely malignant after image fusion. In one patient, image fusion identified uptake in the small bowel as definitely benign. In six patients, malignant lymph nodes (pelvic lymph nodes in four patients, mediastinal nodes in one patient, and supraclavicular nodes in one patient) were additionally verified by biopsy (Fig 1).
Positive AC PET findings in bones. In 11 patients, tracer uptake considered to indicate bone involvement was confirmed by pathologic bone scan in the same location. Positive AC PET findings in other sites. In one patient, a malignant tracer accumulation, which was located to the left anterior thoracic wall, could be identified as an intrapulmonary metastasis with a 1.1-cm diameter after image fusion and was confirmed by CT-guided biopsy. In one patient, cervical uptake judged as malignant did correspond to a cystic lesion of the thyroid after image fusion, but histopathologic evaluation by a biopsy was negative. No malignant uptake was observed in a further follow-up AC PET scan. However, no further specific examinations were performed at that time.
Impact on Patient Management In one patient, AC PET characterized suspicious bone scan uptake as definitely malignant. In two patients, distant lymph nodes (mediastinal and supraclavicular) were detected on AC PET. All three patients were excluded from local salvage radiotherapy and received palliative combined hormonal treatment and radiotherapy. In one patient, AC PET detected one solitary lung metastasis that was treated by stereotactic radiotherapy after confirmation by CT-guided biopsy (Figs 2 and 3).
Given the observation that [18F]FDG PET has limited value for detecting prostate cancer metastases, alternative PET tracers are warranted. Well established in nuclear cardiology, AC is a PET tracer that has recently been introduced for tumor imaging by Shreve et al,18 who reported the tracer's high uptake in renal cell carcinomas. The accumulation of AC in malignant cells is related to the highly active lipid metabolism in the cell membrane associated with tumor growth. AC is channeled into the cancer cycle via acetyl coenzyme A and then incorporated via phosphatidylcholine into the cell membrane's phospholipids. A Japanese group showed marked AC uptake in 22 patients with untreated prostate cancer and metastases and a higher sensitivity of AC PET in detecting prostate cancer compared with [18F]FDG PET.12 More recently, the same Japanese study group,20 as well as Kotzerke et al,25 demonstrated the high sensitivity and specificity of AC PET in diagnosing recurrent prostate cancer, even in the presence of low PSA levels. These encouraging data prompted us to initiate the reported study in patients with PSA recurrence after primary therapy, with the objective of defining the exact localization of recurrent disease and, thus, to offer support in deciding on appropriate treatment. We have to point out that the goal of the reported study was to evaluate the impact of image fusion with conventional morphologic imaging modalities such as CT and MRI. So far, histopathologic stage, Gleason score, and PSA kinetics have offered the key factors to predicting the site of recurrence. Patients with a low Gleason score are most likely to develop local relapse, whereas patients presenting with initially positive lymph nodes or seminal vesicle invasion tend to experience distant metastasis. Furthermore, a local relapse is suspected with a linear increase in PSA values (PSA velocity < 0.75 ng/mL/yr), and generalized disease is suspected when PSA increases show an exponential trend (PSA velocity > 0.75 ng/mL/yr).2 Trapasso et al31 reported median PSA doubling times of 4.3 months in patients with subsequent distant metastasis and 11.7 months in patients with local relapse of disease. However, the PSA doubling time can predict whether patients will have local recurrence or distant metastasis. It cannot indicate the localization of distant failures including bony metastasis and pelvic lymph nodes, which has an important clinical value in choosing the correct therapy. For this purpose, metabolic imaging modalities can be used. Because patients who experience local relapse after radical prostatectomy would draw the greatest benefit from salvage radiotherapy as long as PSA values do not exceed 1.5 ng/mL (American Society for Therapeutic Radiology and Oncology recommendations), radiotherapy is often applied without having visualized the tumor tissue with imaging diagnostics. In our study population, AC PET enabled the visualization of local tumor tissue in six patients, although conventional imaging, including MRI and transrectal ultrasound scan, was negative. Conventional morphologic imaging methods, such as CT and MRI, have been shown to be of limited value in detecting recurrent prostate cancer lesions. They often fail to characterize lymph nodes smaller than 1 cm in diameter; no reliable differentiation between malignant and nonmalignant lymph node enlargements is possible because no information about the metabolic activity indicating a malignancy can be given. We could identify pathologic pelvic lymph nodes in AC PET in four patients without fulfilling typical radiologic signs of pathologic lymphadenopathy on conventional CT. In all four patients, radiation treatment fields could be modified based on these findings. All bone metastases, except that of one patient, would have been detected with bone scan alone in our study group. In these patients, the fusion studies are dispensable. However, bone scan cannot be viewed as a single imaging procedure in patients with increasing or elevated PSA because, despite its high sensitivity, it suffers from low specificity and the inability to detect soft tissue metastases. In five (10%) of 50 patients, a normal AC accumulation was observed, with a median PSA level of 0.9 ng/mL. In these patients, conventional imaging performed in clinical routine (transrectal ultrasound scan, pelvic CT, and bone scan) was normal at that time. In one additional patient, focally increased tracer uptake in the lower pelvis was correlated to the urinary bladder, and no further tracer uptake was observed. Overall, including image fusion in six patients, no malignant uptake was observed. However, in four of the six patients with a PSA ranging from to 2.6 to 13 ng/mL after radical retropubic prostatectomy, AC PET has to be considered as false negative. In two patients with a PSA ranging from 0.5 to 2 ng/mL after external-beam therapy, further follow-up is needed to determine whether these are false-negative AC PET scans. With regard to the (real) sensitivity and specificity of the AC PET study, we have to confess that this was not possible to evaluate because not all lesions found on PET study could be verified by histopathology, which is the main limitation of this study design. Our analysis demonstrated the necessity of combining the advantage of exact anatomic information derived from conventional imaging with the improved tumor information derived from functional PET imaging. Fourteen findings (12 in prostate/prostatic bed and two in lymph nodes) were classified as equivocal on PET images alone. By providing additional anatomic information, the visualization of PET/CT or PET/MRI fusion led to a reclassification of equivocal PET findings as nonmalignant in five of 14 sites and as malignant in nine of 14 sites. These observations are in accordance with data on PET/CT imaging reported recently by Schoder et al26 and Bar-Shalom et al.27 Schoder et al26 reported on two experienced nuclear medicine physicians comparing attenuation-corrected [18F]FDG PET images and PET/CT fusion images, which were performed on combined PET/CT scanners. The authors concluded that PET/CT reduced the number of equivocal (indeterminate) PET interpretations significantly and was particularly helpful in the head and neck as well as the abdomen/pelvis (ie, areas with complex anatomy). Bar Shalom et al27 have stressed the additional impact of simultaneous PET/CT imaging on clinical patient management. Hybrid PET/CT improved the diagnostic interpretation in 49% of cancer patients and had an impact on patient management in 14% of patients. We analyzed the impact of all final PET results on clinical patient management. We showed that final PET findings had an impact on the definition of radiation fields in 10 patients (six including pelvic lymph nodes and four reirradiation to the prostate only). Furthermore, 20 patients were excluded from local salvage radiotherapy by the diagnosis of distant disease. In conclusion, our data suggest that the combined use of PET/CT or PET/MRI fusion images is extremely helpful to determine the exact anatomic location and classification of AC PET findings. Overall, our current approach with retrospective image fusion to identify the sources of PSA elevation in patients after primary treatment of prostate cancer seems to be feasible and applicable in a clinical setting.
The authors indicated no potential conflicts of interest.
Both S.W. and S.T. contributed equally to this work. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Stamey TA, Yang N, Hay AR, et al: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 317:909-916, 1987[Abstract] 2. Partin AW, Oesterling JE: The clinical usefulness of prostate specific antigen: Update 1994. J Urol 152:1358-1368, 1994[Medline] 3. Leibman BD, Dillioglugil O, Wheeler TM, et al: Distant metastasis after radical prostatectomy in patients without an elevated serum prostate specific antigen level. Cancer 76:2530-2534, 1995[CrossRef][Medline] 4. Goad JR, Chang SJ, Ohori M, et al: PSA after definitive radiotherapy for clinically localized prostate cancer. Urol Clin North Am 20:727-736, 1993[Medline] 5. Babaian RJ, Troncoso P, Steelhammer LC, et al: Tumor volume and prostate specific antigen: Implications for early detection and defining a window of curability. J Urol 154:1808-1812, 1995[CrossRef][Medline] 6. Ferguson JK, Oesterling JE: Patient evaluation if prostate-specific antigen becomes elevated following radical prostatectomy or radiation therapy. Urol Clin North Am 21:677-685, 1994[Medline] 7. Seltzer MA, Barbaric Z, Belldegrun A, et al: Comparison of helical computerized tomography, positron emission tomography and monoclonal antibody scans for evaluation of lymph node metastases in patients with prostate specific antigen relapse after treatment for localized prostate cancer. J Urol 162:1322-1328, 1999[CrossRef][Medline] 8. Effert PJ, Bares R, Handt S, et al: Metabolic imaging of untreated prostate cancer by positron emission tomography with 18fluorine-labeled deoxyglucose. J Urol 155:994-998, 1996[CrossRef][Medline] 9. Kanamaru H, Oyama N, Akino H, et al: Evaluation of prostate cancer using FDG-PET. Hinyokika Kiyo 46:851-853, 2000[Medline] 10. Liu IJ, Zafar MB, Lai YH, et al: Fluorodeoxyglucose positron emission tomography studies in diagnosis and staging of clinically organ-confined prostate cancer. Urology 57:108-111, 2001[CrossRef][Medline] 11. Morris MJ, Akhurst T, Osman I, et al: Fluorinated deoxyglucose positron emission tomography imaging in progressive metastatic prostate cancer. Urology 59:913-918, 2002[CrossRef][Medline] 12. Oyama N, Akino H, Kanamaru H, et al: 11C-acetate PET imaging of prostate cancer. J Nucl Med 43:181-186, 2002 13. Oyama N, Akino H, Suzuki Y, et al: FDG PET for evaluating the change of glucose metabolism in prostate cancer after androgen ablation. Nucl Med Commun 22:963-969, 2001[CrossRef][Medline] 14. Oyama N, Akino H, Suzuki Y, et al: The increased accumulation of [18F]fluorodeoxyglucose in untreated prostate cancer. Jpn J Clin Oncol 29:623-629, 1999 15. Sanz G, Robles JE, Gimenez M, et al: Positron emission tomography with 18fluorine-labelled deoxyglucose: Utility in localized and advanced prostate cancer. BJU Int 84:1028-1031, 1999[CrossRef][Medline] 16. Shreve PD, Anzai Y, Wahl RL: Pitfalls in oncologic diagnosis with FDG PET imaging: Physiologic and benign variants. Radiographics 19:61-77, 1999 17. Yeh SD, Imbriaco M, Larson SM, et al: Detection of bony metastases of androgen-independent prostate cancer by PET-FDG. Nucl Med Biol 23:693-697, 1996[CrossRef][Medline] 18. Shreve P, Chiao PC, Humes HD, et al: Carbon-11-acetate PET imaging in renal disease. J Nucl Med 36:1595-1601, 1995 19. Shreve PD, Gross MD: Imaging of the pancreas and related diseases with PET carbon-11-acetate. J Nucl Med 38:1305-1310, 1997 20. Oyama N, Miller TR, Dehdashti F, et al: 11C-acetate PET imaging of prostate cancer: Detection of recurrent disease at PSA relapse. J Nucl Med 44:549-555, 2003 21. Dimitrakopoulou-Strauss A, Strauss LG: PET imaging of prostate cancer with 11C-acetate. J Nucl Med 44:556-558, 2003 22. Kotzerke J, Volkmer BG, Glatting G, et al: Intraindividual comparison of [11C]acetate and [11C]choline PET for detection of metastases of prostate cancer. Nuklearmedizin 42:25-30, 2003[Medline] 23. Fricke E, Machtens S, Hofmann M, et al: Positron emission tomography with (11)C-acetate and (18)F-FDG in prostate cancer patients. Eur J Nucl Med Mol Imaging 30:607-611, 2003[Medline] 24. Hautzel H, Muller-Mattheis V, Herzog H, et al: The (11C) acetate positron emission tomography in prostatic carcinoma: New prospects in metabolic imaging. Urologe A 41:569-576, 2002[CrossRef][Medline] 25. Kotzerke J, Volkmer BG, Neumaier B, et al: Carbon-11 acetate positron emission tomography can detect local recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 29:1380-1384, 2002[CrossRef][Medline] 26. Schoder H, Erdi YE, Larson SM, et al: PET/CT: A new imaging technology in nuclear medicine. Eur J Nucl Med Mol Imaging 30:1419-1437, 2003[CrossRef][Medline] 27. Bar-Shalom R, Yefremov N, Guralnik L, et al: Clinical performance of PET/CT in evaluation of cancer: Additional value for diagnostic imaging and patient management. J Nucl Med 44:1200-1209, 2003 28. Israel O, Keidar Z, Iosilevsky G, et al: The fusion of and physiologic imaging in the management of patients with cancer. Semin Nucl Med 31:191-205, 2001[CrossRef][Medline] 29. Mitterhauser M, Wadsak W, Krcal A, et al: New aspects on the preparation of [11C] acetate: A simple and fast approach via distillation. Appl Radiat Isot 61:1147-1150, 2004[Medline] 30. Lorang TH: Organization and visualization of medical images in radiotherapy. Vienna, Austria, Technische Universitaet Wien, 595,189 II Diss, 2001 31. Trapasso JG, deKernion JB, Smith RB, et al: The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 152:1821-1825, 1994[Medline] Submitted July 25, 2005; accepted January 18, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
, right iliacal lymph node mass; thin, white, right-pointing arrow, bowel loop; thin, white, left-pointing arrow, perirectal lymph node > 1 cm; fat, white arrow, urinary bladder.
