New paper [2] & editorial [1] below. -Patrick
[1] onlinelibrary.wiley.com/doi...
"The search for the ideal imaging method to detect small metastatic deposits has largely remained elusive in the field of prostate cancer. However, functional positron emission tomography (PET)/CT is now guiding us in different directions. 11C-acetate PET/CT imaging was one of the first molecular imaging probes showing promise in clinical studies, along with 11C-choline, and more recently challenged by 68Ga-prostate-specific membrane antigen (PSMA) PET/CT [1-3]. So against this background, what does this new study by Esch et al. [4] presented here offer us?
Let us rewind and focus on where molecular imaging may have an impact in prostate cancer. In primary staging, the potential to accurately identify oligometastatic disease or even widespread metastatic disease before primary gland treatment is clearly advantageous. It can allow for wider treatment fields (extended lymphadenectomy or radiation fields), directed treatment of oligometastatic disease, placement into appropriate cytoreductive trials, and in some instances consideration of the use of earlier chemo-hormonal therapy. This study did not address this important clinical scenario [4]. Nor did it focus on primary diagnosis, another ‘holy grail’ for imaging more recently dominated by MRI [5].
The clinical question addressed in this study was whether 11C-acetate PET is able to detect distant metastatic disease in men with PSA relapse after having undergone radical prostatectomy or prostate bed radiotherapy [4]. In other words, if distant metastatic disease is found then prostate bed radiation may be futile, although this assumption has not been subjected to high quality trials, but would seem logical. Also, in the era of oligometastatic disease, treatment (surgery and/or radiation) may be directed at nodal and other deposits to prolong time of systemic therapy such as androgen-deprivation therapy. So what is the ‘sweet spot’? Some would state for men having undergone surgery a PSA level of 0.2 ng/mL places the patient at risk of recurrence, although in clinical practice the level at which investigations are warranted can be as high as 1.0 ng/mL. This study found 11C-acetate PET had few positive results below a PSA level of 1.0 ng/mL. This is in contrast to a recent meta-analysis of 68Ga-PSMA PET/CT reporting positive studies at PSA levels of ≤0.2 ng/mL in 42% of patients [6].
The other group studied the detection of recurrent disease in men having undergone primary radiotherapy, although the numbers were low (six patients). We know this group of men are often undertreated for salvage treatment, and frequently placed on hormonal therapy. Again, early knowledge of locoregional or distant recurrence is required to allow best case selection and thus avoid futile salvage surgery, and also to know who may benefit from salvage lymphadenectomy and treatment of distant oligometastatic disease, if required.
The false-positive rate result for 11C-acetate PET/CT of 24% is notable and concerning. This may lead to unnecessary intervention, or even withholding prostate bed radiation that may have been of benefit. In contrast the false-positive rate for 11C-choline and 68Ga-PSMA PET/CT is far lower, although false-positive PSMA studies may occur in benign conditions and non-prostate cancer tumours.
It should be acknowledged that a strength of this study was comparative histology in a proportion of patients, allowing true sensitivity and specificity to be determined [4]. This is important information, as it guides correct decision-making, and such information is lacking for many other prostate cancer imaging probes, including 68Ga-PSMA, where these data are urgently required.
Overall, this study is important and adds to the rich milieu of available molecular imaging data on staging of possible recurrent or metastatic prostate cancer to date [4]. Current prospective trials exploring 11C-choline, 18F-FACBC (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid), 18F-choline and 68Ga-PSMA with MRI and clinical outcomes should provide further insight into the most appropriate molecular imaging technique for staging prostate cancer."
.....................................................................
[2] onlinelibrary.wiley.com/doi...
{charts & pictures did not paste below. Click on link for full document.}
Urological Oncology
11C-acetate positron-emission tomography/computed tomography imaging for detection of recurrent disease after radical prostatectomy or radiotherapy in patients with prostate cancer
Authors
Lukas Hendrik Esch,
Melanie Fahlbusch,
Peter Albers,
Hubertus Hautzel,
Volker Müller-Mattheis
First published: 5 December 2016Full publication history
DOI: 10.1111/bju.13706 View/save citation
Cited by (CrossRef): 0 articles Check for updates Citation tools
Article has an altmetric score of 1
Abstract
Objectives
To evaluate, in a prospective study, the effectiveness of computed tomography (CT)-matched 11C-acetate (AC) positron-emission tomography (PET) in patients with prostate cancer (PCa) who had prostate-specific antigen (PSA) relapse after radical prostatectomy (RP) or radiotherapy (RT).
Patients and Methods
In 103 relapsing patients after RP (n = 97) or RT (n = 6) AC-PET images and CT scans were obtained. In patients with AC-PET-positive results with localized PCa recurrence, detected lesions were resected and histologically verified or, after local RT, followed-up by PSA testing. Patients with distant disease on AC-PET were treated with androgen deprivation/chemotherapy.
Results
Of 103 patients, 42 were AC-PET-positive. PSA levels were <1.0, <2.0 and <4.0 ng/mL in six, 16 and 20 patients, respectively. In 25/42 patients AC-PET suggested lymph node metastases: 16/25 patients underwent surgery (10/16 metastasis, 6/16 inflammation); 9/25 patients underwent RT of lymph node metastases, which was followed by decreasing PSA level. In 17/42 patients who had distant disease, systemic treatment was commenced. Combining patients who underwent surgery and those who underwent RT, 19/25 patients were true-positive in terms of AC-PET (positive predictive value 76%). In 5/19 patients, PSA level was <2.0 ng/mL, in 2/19 patients it was <1.0 ng/mL and in 14/19 patients it was 5.4–23.1 ng/mL. In AC-PET-positive patients after surgery or RT (without androgen deprivation), median (range) time to renewed PSA increase was 6 (5–9) months.
Conclusions
Only a minority of patients with relapsing PCa appear to benefit from AC-PET for guiding potential local treatment. False-positive results show that factors other than tumour metabolism induce increased AC uptake. The time free of recurrence after local treatment was shorter than expected.
Introduction
Prostate cancer (PCa) is the most common cancer in men worldwide and is second only to lung cancer in terms of cancer-specific mortality [1]. In the clinical management of PCa, patients with rising PSA levels after definitive local therapy often present a diagnostic dilemma. Patients with local recurrence or limited metastatic lymph node lesions would be amenable to additional local therapy such as salvage prostatectomy, salvage lymph node resection or radiotherapy (RT), thus deferring systemic treatment options, i.e. androgen deprivation therapy (ADT) and/or chemotherapy in this group [2-7]. By contrast, patients with extensive or distant metastases usually require immediate systemic therapy [8]. As with other types of tumour, positron-emission tomography (PET) and PET/CT have emerged almost two decades ago as diagnostic tools for identification of recurrent disease in PCa [9]. Several radiotracers have been under investigation for this purpose after the widely used 18-F-fluorodeoxyglucose (FDG)-PET was found to have only limited abilities in PCa imaging [10, 11]. Among the non-FDG tracers, 11C/18F-choline, 11C-acetate (AC) and, most recently, 68 Ga-PSMA have been the subjects of various studies. Although choline-based tracers showed superior sensitivity compared with FDG (47 vs 27%) [12], accuracy is largely dependent on PSA value/PSA doubling time [13], with detection rates as low as 28% and 36% being reported for PSA values of <1 ng/mL and 1.5 ng/mL, respectively [14, 15]. This limits the role of choline PET/CT in the management of recurrent PCa.
Similarly to choline-based radiotracers, radioactive labelled acetate is predominantly incorporated into lipid cell membranes of PCa cells by making use of the overexpression of fatty acid synthase in this disease [16-21]. Its role in the detection of recurrent disease after radical prostatectomy (RP) or RT in patients with PCa has not yet been fully defined and is subject to ongoing research. In the present prospective study, we evaluated the effectiveness of AC-PET matched with corresponding CT scans in patients with PSA relapse after RP or RT.
Patients and Methods
Study approval was granted by the German Federal Office on Radiation Protection (Bundesamt für Strahlenschutz), Berlin, and the local ethics committee. A total of 103 patients (mean [range] age 69 [61–78] years) with histologically confirmed PCa and rising PSA values after RP (n = 97) or RT (n = 6) were prospectively enrolled in this study. All patients gave written informed consent before undergoing imaging. Five minutes after i.v. administration of 705 ± 134 MBq, AC-PET images from the pelvic floor to the neck were obtained using a Siemens ECAT Exact HR+ scanner (Siemens, Knoxville, TN, USA). All PET images were attenuation-corrected, reconstructed with standard iterative algorithms and reformatted into transverse, coronal and sagittal views. A CT scan from the neck to the pelvic floor was performed additionally. An image overlay of corresponding CT and PET scans was carried out using the dedicated image software Multi Purpose Imaging tool (MPI tool, Advanced Tomo Vision GmbH, Kerpen, Germany; Fig. 1). Standardized uptake values were calculated using attenuation-corrected PET data. In all PET-positive patients who were found to have local lymph node metastases the detected lesions were resected and histopathologically verified (Fig. 2), or follow-up examinations (PSA controls every 3 months) were performed after local RT. In those patients with advanced metastatic disease, i.e. bone, distant lymph node or visceral metastases, systemic therapy in the form of ADT or chemotherapy was initiated. For data analysis, ‘true-positive’ patients were defined as patients with PET-positive results who had either confirmed metastases on resection or a decrease in PSA level after local RT as well as after systemic treatment for advanced metastatic disease. ‘False-positive’ patients were defined as those with PET-positive results with inflammation on resection or patients without a decrease in PSA level after local RT as well as systemic treatment. Positive predictive value was calculated as the sum of PET-positive patients with confirmed metastases as well as a PSA decrease after RT/systemic treatment divided by the total number of PET-positive patients. More specifically, positive predictive value was also calculated in identical fashion for the detection of local lymph node metastases in the subgroup of PET-positive patients who underwent surgical resection and local RT.
Figure 1.
Figure 1. Open in figure viewerDownload Powerpoint slide
Pelvic lymph node recurrence on merged positron-emission tomography (PET)/CT: PET images reconstructed and reformatted into coronal view (middle), image overlay of corresponding CT scans (left) using a specific image software, creating a merged PET/CT image (right; Development: Max-Planck-Institute, Cologne/Germany). Increased tracer uptake in an enlarged right iliac lymph node, later histologically confirmed to be prostate cancer metastasis.
Figure 2.
Figure 2. Open in figure viewerDownload Powerpoint slide
Robot-assisted laparoscopic resection of lymph node metastasis.
Results
Of 103 patients, 42 were considered PET-positive (Fig. 3). PSA levels in six patients in this subset were <1.0 ng/mL, in 16 patients they were <2.0 ng/mL and in 20 patients they were <4.0 ng/mL. In the subset of PET-negative patients, 18 had PSA values >4.0 ng/mL (Figs 4 and 5).
Figure 3.
Figure 3. Open in figure viewerDownload Powerpoint slide
Algorithm of the study. ADT, androgen deprivation therapy; PPV, positive predictive value; RT, radiotherapy, RP, radical prostatectomy.
Figure 4.
Figure 4. Open in figure viewerDownload Powerpoint slide
PSA distribution of PET positive patients at time of AC-PET.
Figure 5.
Figure 5. Open in figure viewerDownload Powerpoint slide
PSA distribution of positron-emission tomography (PET)-negative patients at time of 11C-acetate (AC)-PET.
Analysis of the PET-positive patients showed that in 25 of 42 cases AC-PET indicated isolated lymph node metastases, whereas PET suggested advanced metastatic disease in 17 of 42 patients. Within the former subgroup of 25 AC-PET positive patients suggesting local recurrence, imaging findings were histopathologically verified in 16 patients. 10 out of 16 lesions were confirmed to be PCa metastases, while in six of 16 lesions unspecific inflammatory tissue alterations were identified. In the remaining nine of 25 patients subsequently undergoing RT for radiomorphologically identified lymph node metastases the PSA level decreased after localized salvage therapy; therefore, AC-PET in all these irradiated patients was rated as true-positive. Seventeen of 42 patients with PET-positive results suggestive of advanced metastatic disease were treated with either ADT (15/17) or docetaxel chemotherapy after induction of ADT (2/17). As a consequence of response to treatment as indicated by a reduction of PSA levels, final assessment of the AC-PET results in these patients was also true-positive.
In summary, 36 of 42 PET-positive patients were therefore deemed to be true-positives. Consequently, the positive predictive value for overall detection of recurrence in AC-PET-positive patients was 85.7% (36 of 42).
With respect to the patients who underwent either surgery or RT (n = 25) there were 19 of 25 true-positives in terms of AC-PET. In five of these 19 patients PSA level was <2.0 ng/mL, and only in two of 19 patients, PSA level was <1.0 ng/mL. In the remaining 14 patients, PSA distribution ranged from 5.4 to 23.1 ng/mL. The median PSA doubling time in PET-positive cases was 123 days, while in PET-negative cases it was 248 days. Positive predictive value for detection of local lymph node metastasis in AC-PET-positive patients was 76% (19 of 25). In those AC-PET-positive patients having undergone surgery or local RT (without ADT), the median (range) time to renewed increase in PSA level was 6 (5–9) months.
Discussion
In the present prospective study, we evaluated the role of AC-PET/CT imaging for detection of recurrent disease after RP or RT. AC-PET was capable of correctly detecting local PCa recurrence even in patients with low PSA levels (<1.0 ng/mL in two of 19 true-positive cases and <2.0 ng/mL in five of 19 true-positive cases), thus confirming the potential usefulness of AC-PET in patients with relapsing PCa suggested by former studies [19-21]. In the present study we calculated a positive predictive value for the detection of local lymph node metastasis by AC-PET of 76%; therefore, this imaging tool is able to provide some additional information when making fundamental clinical decisions in the management of this challenging patient group, i.e. choosing local therapy rather than systemic ADT and/or chemotherapy.
Despite these encouraging findings, the use of AC in this setting is accompanied by several shortcomings of this radiotracer. The sensitivity of AC-PET in PCa relapse remained strongly related to PSA value, which is consistent with previous studies as well as a recent meta-analysis which reported a sensitivity as low as 28% in patients with PSA values <1 ng/mL compared with 63% in those with PSA values >1 ng/mL [22]. In the present study only six of 40 patients (15%) with PSA values <1 ng/mL were AC-PET-positive, while the remaining 34 of 40 patients were deemed negative at this PSA level. Furthermore, limitations regarding the specificity of AC need to be considered. In the present study we found six of 25 positive patients (24%) had negative histology on resection i.e. 6/25 false positives; therefore, one must assume that factors other than tumour metabolism may cause significant AC uptake, resulting in a reduced specificity/positive predictive value of AC-PET.
Overall, the results of the present series are consistent with findings of previously published studies, as well as with a recent review and meta-analysis, which reported a pooled sensitivity of 64 (59–69)% and a pooled specificity of 93 (83–98)% in relapsing PCa [22]. However, later results are limited by the highly heterogeneous nature of the studies included in this meta-analysis, in terms of sample size, PSA range and study design. With a median recurrence-free period of only 6 months the efficacy of treating local relapse by surgery or RT is limited and contradicts previous reports of progression-free survival of up to several years [3-7]. When setting AC-PET results in context with 11C/18F-choline studies, a similarly poor performance, especially in the low PSA ranges, is noted, with detection rates of radiolabelled choline reported to be as low as 21, 28 and 44% for PSA levels of <0.5, <1.5 and <2 ng/mL, respectively [15, 23, 24]
When comparing these results with studies using 68 Ga-PSMA-PET, a generally higher sensitivity and specificity for this novel tracer can be observed; a recent evaluation of 68 Ga-PSMA-PET in 248 patients with biochemical recurrence after RP reported an overall detection rate of 89.5%, ranging from 57.9% for PSA levels ≤0.5 ng/mL to as high as 96.8% for PSA levels of ≥2 ng/mL [25]. These results are in line with similar studies examining this tracer [26, 27]; however, it should be noted that the ‘gold standard’ for histopathological confirmation of imaging findings was only applied in a small minority of the study population (i.e. 12 of 248 [25] and 42 of 319 [26] patients, in the studies mentioned). An unknown number of false-positive findings must therefore be considered when interpreting these results. The highest level of evidence regarding 68 Ga-PSMA-PET characteristics can be derived from a most recently published systematic review and meta-analysis [28]: the overall percentage of positive 68 Ga-PSMA-PET in patients with PCa relapse was 76%. For the PSA categories 0–0.2, 0.2–1, 1–2 and >2 ng/mL, 42, 58, 76 and 95% scans, respectively, were positive. Despite the limited history of this emerging tracer, pooled data indicate favourable sensitivity and specificity of 68 Ga-PSMA compared with choline-based imaging techniques as well as the AC-PET used in the present study. The apparently higher detection rate at low PSA categories compared with choline as well as AC-PET, however, makes 68 Ga-PSMA-PET an encouraging candidate in the search of an ideal tracer. In contrast to formerly used tracers, 68 Ga-PSMA targets a PCa-specific tissue structure rather than unspecific metabolic changes induced by the tumour growth.
Apart from characteristics of the radiotracer AC used in the present study, several aspects of the study design might have influenced its results. Rather than using a hybrid PET/CT scanner that acquires images from both devices sequentially and in the same session, for the present study PET images were merged with corresponding CT scans using dedicated software. Detection rates/sensitivity as well as spatial resolution might therefore have been negatively affected by inferior software algorithms or alterations in the examination setting/patient's positioning between individual PET and CT scans.
Furthermore, the study is limited by the relatively heterogeneous nature of the study population in terms of previous or concomitant therapy, PSA level at the time of PET/CT, treatment approach and follow-up. AC-PET-negative findings were not systematically confirmed by biopsy in order to account for false-negative PET findings; therefore, only very limited conclusions regarding the sensitivity, specificity and negative predictive value of AC-PET in PCa relapse can be drawn from this study. The ideal study subjects would have been patients without any kind of (neo)adjuvant treatment who had a PSA nadir of <0.01 ng/mL after RP and presented promptly after diagnosis of biochemical recurrence with PSA values <2.0 ng/mL. Recruiting a sufficient number of these ideal candidates for the present study turned out to be infeasible within a reasonable study period.
In conclusion, for a limited subset of patients, AC-PET seems to be a useful tool in the detection of recurrent PCa, but false-positive findings show that factors other than tumour metabolism can lead to an increased AC uptake. There is still a need, therefore, for a more PCa-specific tracer. Recent studies using emerging 68 Ga-PSMA-PET have had promising results, with favourable detection rates for low PSA categories. 68 Ga-PSMA might therefore be able to overcome those shortcomings and provide a more accurate assessment when dealing with this challenging disease. We await long-term data after local treatment of PET-identified lesions before promoting this approach to patients.
Help interpreting PMSA Pet scan
C-11 Choline Pet Scan
Game changer in diagnosis?
CT PET efficiency with PSMA, c11 choline and axumin 
