SEARCH

SEARCH BY CITATION

Keywords:

  • prostate cancer;
  • 11C-acetate;
  • PET;
  • systematic review;
  • meta-analysis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  • To review the literature on the application of 11C-acetate positron-emission tomography (PET) imaging in prostate cancer.
  • We systematically reviewed the available literature and presented the results in meta-analysis format.
  • PubMed, SCOPUS, ISI web of knowledge, Science Direct, Springer, and Google Scholar were searched with ‘Acetate AND PET AND Prostate’ as keywords.
  • All studies that evaluated accuracy of 11C-acetate imaging in primary or recurrent prostate cancer were included, if enough data could be extracted for calculation of sensitivity and/or specificity.
  • In all, 23 studies were included in the study. For evaluation of primary tumour, pooled sensitivity was 75.1 (69.8–79.8)% and specificity was 75.8 (72.4–78.9)%.
  • For detection of recurrence, sensitivity was 64 (59–69)% and specificity was 93 (83–98)%. Sensitivity for recurrence detection was higher in post-surgical vs post-radiotherapy patients and in patients with PSA at relapse of >1 ng/mL.
  • Studies using PET/computed tomography vs PET also showed higher sensitivity for detection of recurrence.
  • Imaging with 11C-acetate PET can be useful in patients with prostate cancer. This is especially true for evaluation of patients at PSA relapse, although the sensitivity is overall low.
  • For primary tumour evaluation (localisation of tumour in the prostate and differentiation of malignant from benign lesions), 11C-acetate is of limited value due to low sensitivity and specificity.
  • Due to the poor quality of the included studies, the results should be interpreted with caution and further high-quality studies are needed.

Abbreviations
AUC

area under the curve

DOR

diagnostic odds ratio

FDG

fluorodeoxyglucose

LR

likelihood ratio

PET

positron-emission tomography

RT

radiotherapy

SROC

summary receiver operating characteristics curve

SUV

standardised uptake value

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Prostate cancer is among the most frequent male cancers and is second to lung cancer as the main cause of cancer death [1, 2]. Staging of newly diagnosed prostate cancer is of utmost importance, as treatment planning is highly dependent on correct staging [2, 3]. In addition to primary tumour staging, detection of tumour location in patients with a suspicion of recurrence (rising PSA levels) is another challenge to treating physicians [4].

Diagnosis of primary or recurrent prostate cancer is usually dependent on clinical examination, PSA, and radiological studies, i.e. ultrasonography, CT, and MRI. However, the above-mentioned methods are not sensitive and specific enough [5] and other imaging methods are being sought actively for this purpose.

Similar to other urological tumours [6], positron-emission tomography (PET) imaging has been used for evaluation of primary or recurrent prostate cancer. However, 18F-fluorodeoxyglucose (FDG) was not sensitive enough and several non-FDG tracers are now currently being study for this purpose including 11C- and 18F-choline and 11C-acetate [4]. 11C-acetate in the tumour cells is incorporated into the membrane lipids due to over-expression of fatty acid synthase. This property is exploited for tumour imaging with 11C-acetate [7]. Fatty acid synthase is particularly over-expressed in prostate cancer cells and 11C-acetate has been especially used for evaluation of this tumour [3]. In addition, elimination route of 11C-acetate is through the respiratory system and imaging can be performed without interference of urinary activity. In the present study, we systematically reviewed the available literature on the application of 11C-acetate PET imaging in prostate cancer and presented the results in meta-analysis format.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

‘Acetate AND PET AND Prostate’ were used as keywords to search the literature. PubMed, SCOPUS, ISI web of knowledge, Science Direct, Springer, and Google Scholar were searched and the last search was done in March 2013. No language limit was applied and meeting abstracts were not excluded either. Studies evaluating 11C-acetate PET imaging for prostate cancer were included. The reference lists of the retrieved studies were hand searched for possible missing relevant articles. We contacted the corresponding authors when necessary.

All studies evaluating the accuracy of 11C-acetate imaging in primary or recurrent prostate cancer were included, if enough data could be extracted for calculation of sensitivity and/or specificity. Case reports, review articles, and editorial materials were excluded. Two authors reviewed the retrieved articles independently. A third author opinion was used in cases of any controversy. Duplicate studies were discussed and only the most recent reports were included.

The quality of the included studies was checked using the Oxford Centre for Evidence-Based Medicine checklist for diagnostic studies by two authors [8].

Data abstraction was done by two of the authors independently, and information on the study authors, publication year, method, patient characteristics, quality of the study, sensitivity and/or specificity (if possible in different anatomical locations) were recorded.

The Devillé et al. [9] recommendations for diagnostic studies meta-analysis were followed. The random-effects model (DerSimonian and Laird method [10]) was used for pooling the results. Forrest plots were used for graphical presentation of the results. For heterogeneity evaluation the Cochrane's Q test was used, and the significance level was set at P = 0.05. For quantifying the heterogeneity, the I2 index was used. The I2 index shows how much of the variability of diagnostic indices (i.e. sensitivity or specificity) between studies is real and not merely due to sampling errors of the included studies. This variability can be due to different designs, spectra of included patients, etc. among the included studies. A higher I2 index means more variability among the studies.

One of the major sources of heterogeneity in the diagnostic studies is the threshold effect. Each diagnostic study usually has its own threshold value of positivity. This may or may not be mentioned by the authors in the included studies. Changing the threshold will cause reciprocal changes in the sensitivity and specificity: strict thresholds would result in high specificity but lower sensitivity and vice versa. A strong correlation between the sensitivity and specificity of the included studies denotes an important threshold effect. In the present study, the threshold effect was evaluated using the correlation between false positive and true positive rates in the included studies [11]. For studies with enough information about the thresholds of 11C-acetate PET positivity, different thresholds were imposed, and new diagnostic indices were re-calculated. Sensitivity, specificity, negative likelihood ratio (LR–), positive LR (LR+), and diagnostic odds ratio (DOR) were calculated for each study, and pooling was done for each. Besides DOR, summary receiver operating characteristics curve (SROC) fitting [11], area under the curve (AUC) calculation, as well as Q* value [12] were used for summarising overall accuracy. The SROC is a way to present overall accuracy of a diagnostic test. Closer values of the AUC to 1 mean better performance.

Funnel plots, Egger's regression intercept [13], and Duval and Tweedie's ‘trim and fill’ method [14] were used for publication bias evaluation. Funnel plots are plots of the diagnostic indices (sensitivity or specificity in the present study) against standard errors and any asymmetry in the funnel plots can be due to important publication bias. Egger's regression intercept is the statistical method for evaluation of funnel plots asymmetry. In the ‘trim and fill’ method, a symmetrical funnel plot is achieved after trimming of studies and adjusted diagnostic indices for possible publication bias are re-calculated. The new adjusted diagnostic indices show how important the possible publication bias can be. More discrepancy between the original and the adjusted values shows more important publication bias.

All statistical analyses were done using Meta-Disc (version 1.4) [15] and Comprehensive Meta-analysis (CMA version 2).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

Figure 1 shows the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flowchart of the study search strategy. Overall, the first search yielded 112 studies; 46 studies were excluded by screening of titles and abstracts. The remaining 66 citations were evaluated in more detail; 42 studies were excluded at this stage for being letters to editors, case reports, narrative review articles, or due to incomplete data. Finally, 24 studies were included in the systematic review [16-39]. Table 1 shows the characteristics of included studies [16-39].

figure

Figure 1. PRISMA flowchart of the study search strategy.

Download figure to PowerPoint

Table 1. Summary of the included studies information
ReferencePublication yearAim of the imagingImaging methodImaging time after injection, minMean age, yearsMedian (range) Gleason ScoreMean (range) PSA level, ng/mLDose, MBqPrimary treatment of the tumour in studies for re-stagingSpectrum of the patientsClear explanation of the studyGold standardConsecutive recruitmentLevel of evidence*Threshold value for positivity of PET imaging
  1. *Level of evidence according to Oxford Centre for Evidence-Based Medicine; BT, brachytherapy; RP, radical prostatectomy.

Oyama et al. [16]2002StagingPET10–2071.85.66N/A740N/APatients with diagnosed prostate cancerYesHistology, ImagingN/A3N/A
Oyama et al. [19]2003Re-stagingPETImmediately65.67.6 (7–10)4.88 (0.3–47.5)1110SurgeryPatients suspicious of recurrenceYesHistology, Imaging (CT scan, Bone scan)N/A3N/A
Kato et al. [17]2002Imaging of the primary tumour in the prostatePETImmediately46.6N/A1790 (0.3–6954)555N/APatients with diagnosed prostate cancer, BPH, or normal prostateYesHistologyN/A3SUV >2
Kotzerke et al. [18]2002Re-stagingPET5708 (4–9)11.9 (0.1–150.6)810 ± 250SurgeryPatients suspicious of recurrenceYesHistology (21 patients), TRUS, Other imaging modalities, Bone scintigraphy, Follow upN/A3N/A
Fricke et al. [20]2003Re-stagingPETImmediately66.247 (3–9)44.9710MBq/kgN/APatients suspicious of recurrenceYesHistology, CT, MRI and/or TRUSN/A3SUV >2
Kotzerke et al. [21]2003Staging and re-stagingPET5727 (4–9)10.9 (0.1–54)950 ± 150SurgeryPatients suspicious of recurrence or diagnosed as prostate cancer for stagingYesHistology and imaging, TRUSN/A3Moderate or severe increased uptake
Alavi et al. [22]2003Re-stagingPETN/AN/AN/AN/A500–700SurgeryPatients suspicious of recurrenceNoHistology (10 patients), CT, MRI, Bone scanYes3N/A
de Jong et al. [23]2003Imaging of the primary tumour in the prostatePET564.56 (6–8)15.2 (1.8–6.8)800N/APatients with proven prostate cancer and BPHYesHistologyNo3N/A
Seltzer et al. [24]2003Re-stagingPETN/A66N/A2 (0.2–153)N/ARTPatients suspicious of recurrenceNoHistology, CT, Bone scanN/A3N/A
Manente et al. [25]2005Re-stagingPET/CT566(4–9)(0.5–21.9)555Surgery (31) BT (2)Patients suspicious of recurrenceYesHistology (2 patients), MRI, Clinical and instrumental evaluationN/A3N/A
Albrecht et al. [26]2007Re-stagingPET/CTone set at 2 min (early images) and another at 47 min after injection (late images)65.2 (after surgery) and 72.5 (after RT)71.17 (0.19–4.8) (after-surgery), 10.4 (2.6–30.2) (after RT)520RT and surgeryPatients suspicious of recurrenceYesHistology (6 patients), Imaging (CT, MRS, Bone scan), Follow upYes3SUV >2
Vees et al. [27]2007Re-stagingPET/CT26470.3 (0.08–0.76)524 ± 24SurgeryPatients suspicious of recurrenceYesImaging (CT, MRI, Bone scan), Follow upYes2Lesions with uptake considerably higher than background
Sandblom et al. [28]2006Re-stagingPET/CT1055–777 (3–9)2 (0.5–8.1)800SurgeryPatients suspicious of recurrenceYesHistology, CT, Bone scanN/A3N/A
Wachter et al. [29]2006Re-stagingPET fused with separate CT images1566N/A

6.3 (after-RP), 12.4 (after RT),

9.9 (BT)

740

Surgery (34),

RT (12),

BT (4)

Patients suspicious of recurrenceYesHistology (17 patients), MRI, CT, Bone scanN/A3N/A
Schumacher et al. [30]2009Staging (lymph node)PET/CT 24, PET 6N/A637 (5–9)18 (2–98)N/AN/APatients with diagnosed prostate cancerNoHistology (pelvic lymph node dissection)Yes2High uptake compared with surrounding tissues
Han et al. [31]2009Imaging of the primary tumourPET/CTN/AN/AN/AN/AN/AN/APatients with diagnosed prostate cancerNoHistologyYes2N/A
Arenas et al. [32]2009Imaging of the primary tumourPET/CTN/AN/AN/AN/AN/AN/APatients with diagnosed prostate cancerNoHistologyN/A3N/A
Vees et al. [33]2009Re-stagingPET/CT5, 21, and 45N/AN/A<0.5N/ARTPatients in clinical remission after RTNoClinical judgmentN/A4N/A
Oyama et al. [34]2010Re-stagingPETN/AN/AN/A7 <1; 6 < 1 < 3; 3 >3370SurgeryPatients suspicious of recurrenceNoHistology, CT, Bone scintigraphyN/A3N/A
Yu et al. [35]2011Re-staging (bone recurrence)PETImmediateN/A8414 (6.3–2010)107/kg

Surgery (5) RT (2)

BT (1)

Patients with >3 bone metastasesYesBone scintigraphy, CT scanN/A3SUV >2
Müller-Mattheis et al. [36]2011Re-stagingPET fused with separate CT imagesN/A69N/A5.31000Surgery (40) RT(6)Patients suspicious of recurrenceYesHistology, CT, Follow upN/A3SUV >2
Jambor et al. [37]2012Imaging of the primary tumour in the prostatePET/CT10666 (3–9)9.8 (2.9–30)658 ± 105N/APatients with diagnosed prostate cancerYesHistologyN/A3N/A
Mena et al. [38]2012Imaging of the primary tumour in the prostatePET/CTImmediately (dynamic imaging for 30 min)587 (6–9)7.03 (1.07–53.5)1472 (1176–2545)N/APatients with diagnosed prostate cancerYesHistologyN/A3N/A
Haseebuddin et al. [39]2013StagingPET/CTImmediately after completion of CT61 (median)7 (6–10)11.8 (median) (1.4–225.4)740 or 1480N/APatients with newly diagnosed prostate cancer with intermediate to high risk of lymph node metastasisYesHistologyN/A3Patients with higher than 2+ uptake. No SUV value mentioned.

Primary Tumour Evaluation

The studies reported accuracy of 11C-acetate for primary tumour detection in two ways: patient basis and lesion basis. Nine studies reported on the patient basis [16, 17, 21, 23, 31, 32, 37-39] and three studies reported on the lesion basis [31, 37, 38]. Among studies reported on the patient basis, only de Jong et al. [23] reported a specificity of 60% (three out of five patients). We extracted data on both information and the results are shown in Table 2.

Table 2. Accuracy of C11-acetate for evaluation of primary tumour
 Sensitivity, %HeterogeneitySpecificity, %HeterogeneityLR+HeterogeneityLR-HeterogeneityDORHeterogeneity
I2 index, %Cochrane test PI2 index, %Cochrane test PI2 index, %Cochrane test PI2 index, %Cochrane test PI2 index, %Cochrane test P
Lesion basis75.1 (69.8–79.8)94.5<0.00175.8 (72.4–78.9)95.2<0.0012.044 (1.303–3.204)89<0.0010.311 (0.156–0.619)75.50.0176.712 (4.826–9.335)00.563
Patient basis93 (90–96)74.7<0.001

Subgroup analysis was possible for the type of instrument (PET or PET/CT) used in the studies reported on the patient basis: sensitivity was 90 (77–93)% for the PET group and 94 (90–97)% for the PET/CT group.

Threshold analysis for the studies reported on the lesion basis showed a moderate correlation between sensitivity and specificity (correlation coefficient –0.5, P = 0.667). SROC analysis showed an AUC of 0.78 and Q* of 0.72. The included studies usually used a standardised uptake value (SUV) of >2 as the threshold value of positivity. Changing the threshold value to a lower point in the studies that reported the relevant information (SUV >1) resulted in higher sensitivity of 94 (89–97)% for the patient basis studies.

Publication bias evaluation showed asymmetric funnel plot for sensitivity pooling (not shown). The Egger's regression intercept was 2.06 (P = 0.048).

Primary Tumour: Lymph Node Staging

Oyama et al. [16] and Haseebuddin et al. [39] reported sensitivity of lymph node staging with 11C-acetate with pooled sensitivity of 73 (54–88)% (I2 = 71%). Three studies reported specificity of lymph node staging with 11C-acetate [23, 30, 39] with resulting pooled specificity of 79 (72–86)% (I2 = 78.3%).

Recurrence Overall

In all, 14 studies reported accuracy of 11C-acetate PET imaging for evaluation of recurrence in patients with evidence of PSA relapse (either after surgery or after radiotherapy, RT) [18-22, 24-29, 33, 34, 36]. Figure 2 shows the forest plots of sensitivity and specificity pooling. Table 3 shows the remaining pooled diagnostic indices.

figure

Figure 2. Forest plots of sensitivity (top) and specificity (bottom) pooling for overall recurrence.

Download figure to PowerPoint

Table 3. Diagnostic indices of C11-acetate PET imaging for evaluation of patients with evidence of PSA relapse
LR+HeterogeneityLR–HeterogeneityDORHeterogeneity
I2 index, %Cochrane test PI2 index, %Cochrane test PI2 index, %Cochrane test P
1.774 (0.642–4.906)89<0.0010.449 (0.216–0.934)70.90.0013.876 (0.607–24.755)74.2<0.001

Threshold analysis showed a moderate correlation between sensitivity and specificity (correlation coefficient –0.41, P = 0.27). SROC analysis is shown in Fig. 3 (AUC 0.73 and Q* 0.68). As mentioned for primary lesion evaluation, the threshold used for most of the studies was SUV >2. We re-calculated the accuracy of 11C-acetate for studies if SUV >1 was used as the threshold. The resulting pooled sensitivity and specificity were 68 (63–83)% and 91 (81–97)%, respectively.

figure

Figure 3. SROC curve for the accuracy of 11C-acetate for evaluation of overall recurrence.

Download figure to PowerPoint

Effects of several variables on the accuracy of 11C-acetate imaging were evaluated using subgroup analyses and meta-regression, which are shown in Table 4.

Table 4. Effect of the confounding variables on the accuracy of C11-acetate PET imaging for evaluation of patients with evidence of PSA relapse
 InstrumentPrimary treatmentPSA value, ng/mLMean age of the patients, slopeDose of the tracer, slope
PETPET/CTSurgery (total prostatectomy)RT>1<1
Sensitivity, %55.1 (48.8–61.3)83.1 (75.3–89.2)71.6 (63.6–78.7)50.9 (41.2–60.6)63.8 (54.8–72.1)28.6 (16.6–43.3)–0.005–0.002
Specificity, %94.7 (74–99.9)92.3 (79.1–98.4)89.5 (75.2–97.1)96.2 (80.4–99.9)0.170.002

Publication bias evaluation showed asymmetric funnel plots on visual examination for sensitivity and specificity pooling (Fig. 4). Egger's regression intercepts for sensitivity and specificity pooling were 2.24 (P = 0.12) and 2.84 (P = 0.03), respectively. Duval and Tweedie's trim and fill method showed 1.6% decrease in sensitivity and 8.9% decrease in specificity after trimming one study for each.

figure

Figure 4. Funnel plots of sensitivity (top) and specificity (bottom) pooling for overall recurrence.

Download figure to PowerPoint

Recurrence according to the Site (Local, Distant, Lymph Nodes)

The pooled diagnostic indices for evaluation of patients with PSA relapse considering the site of recurrence are shown in Table 5.

Table 5. Accuracy of C11-acetate for evaluation of patients with evidence of PSA relapse considering the site of recurrence
Site of recurrenceSensitivity, %Specificity, %LR+LR–DORAUCQ*
Local64.4 (55.6–72.5)96.3 (89.6–99.2)7.36 (1.41–38.22)0.34 (0.13–0.83)26.70 (2.49–286.06)0.970.93
Distant (mostly bone)81.6 (65.7–92.3)98.8 (93.7–100)18.64 (5.9–58.83)31.3 (0.123–0.8)63.97 (14.12–289.7)0.990.98
Regional lymph nodes81.5 (61.9–93.7)94.4 (88.2–97.9)10.6 (5.12–21.93)0.26 (0.14–0.49)54.92 (12.07–249.93)0.950.89

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References

In the present study, we evaluated the application of 11C-acetate PET imaging in prostate cancer. We divided our discussion into two parts: staging of prostate cancer and restaging in patients with PSA relapse.

Staging of Prostate Cancer

Primary prostate cancer

Several studies reported the sensitivity of 11C-acetate imaging for detection of primary prostate cancer. The pooled sensitivity of these studies was 93 (90–96)%. The specificity was only evaluated by de Jong et al. [23], who reported high uptake of 11C-acetate in BPH similar to prostate cancer. However, more useful data would be a lesion basis approach that reported the accuracy of 11C-acetate imaging according to the lesions (or different sections of each prostate). Pooled diagnostic indices were sub-optimal: 75.1 (69.8–79.8)% sensitivity and 75.8 (72.4–78.9)% specificity. This is because of the inability of 11C-acetate PET imaging to show small tumours and high uptake of this radiotracer in the patients with BPH [17, 38]. According to the present results, 11C-acetate cannot be used for differentiation of prostate cancer from other abnormalities of prostate (due to sub-optimal specificity). Its use for intraprostatic localisation of prostate cancer lesions is also limited due to sub-optimal sensitivity.

Lymph node staging

Lymph node staging is of utmost importance for prostate cancer treatment planning [40]. 11C-acetate has been used in limited studies for this purpose. Pooled sensitivity was suboptimal, at 73 (54–88)%, which can limit its utility. However, Haseebuddin et al. [39] reported that 11C-acetate PET/CT could detect lymph node metastasis not identified by conventional imaging and can be used as a complementary imaging method. False positive results have also been reported [30, 39] with resulting sub-optimal specificity of 79 (72–86) %.

Factors affecting the results of 11C-acetate PET imaging in primary prostate cancer

Studies using PET/CT reported slightly higher sensitivity than those that used PET alone. This can be due to the addition of anatomical details using PET/CT [37]. Threshold effect was also evaluated and by decreasing the threshold value, sensitivity increased by 3%.

PSA level and Gleason score did not seem to affect the 11C-acetate uptake in prostate cancer lesions as reported by Oyama et al. [16] and Mena et al. [38].

The time of imaging was not related to the 11C-acetate PET results either [17], although Mena et al. [38] reported peak radiotracer uptake 10 min after injection.

Restaging in Patients with PSA Relapse

Correct localisation of relapse is very important in the follow-up of the patients with prostate cancer, as treatment planning is highly dependent on this localisation. Overall, 11C-acetate PET could localise the location of relapse with pooled sensitivity of 64 (59–69)% and pooled specificity of 93 (83–98)%. However, the included studies were highly heterogeneous as shown by high I2 indices in Table 3. To account for these heterogeneous results, we performed subgroup analyses as well as meta-regression. As shown in Table 4 several variables can affect the results of 11C-acetate PET.

PET/CT showed higher sensitivity than PET imaging alone. This is due to incorporation of anatomical details into the interpretation of PET imaging, which can decrease the ambiguous results as reported by Wachter et al. [29] who compared PET-only and fused images of PET with CT.

The primary treatment of the patients (total prostatectomy vs RT) also could affect the 11C-acetate imaging dramatically as post-surgical patients had 20% higher sensitivity than the post-RT patients. RT does not ablate the whole prostate gland in contrast to total prostatectomy, this can be the reason of better performance of 11C-acetate PET in post-surgical relapse, as any residual tissue in the prostatic bed can be detected more readily without interference of non-tumoral prostate tissue [19, 26].

PSA value was strongly related to the sensitivity of 11C-acetate imaging in prostate cancer relapse. Patients with a low PSA value (PSA <1 ng/dL) had 35% lower sensitivity than those with PSA value of >1 ng/dL. This may be due to higher tumour burden in patients with higher PSA values, which results in better visualisation by 11C-acetate imaging. Fricke et al. [20] also reported a high correlation betweenPSA level and 11C-acetate uptake in the tumoral tissues at relapse. In another study, Seltzer et al. [24] evaluated the PSA velocity effect on 11C-acetate accuracy and reported higher sensitivity for higher PSA velocity.

The mean age of the patients and 11C-acetate dose had a very low and clinically insignificant correlation with sensitivity and specificity of the 11C-acetate imaging as shown in Table 4. These two variables do not seem to affect the accuracy of 11C-acetate imaging for detection of relapse.

Time of imaging (early vs delayed) after radiotracer injection was evaluated by two separate studies [26, 33]. Vees et al. [33] reported less equivocal results when interpreting early and delayed images together compared with early images alone, which was also supported by the Albrecht et al. [26] results. It seems that in cases of equivocal results on the early imaging, late images (at 45 min after injection) may be beneficial.

Threshold effect is always a concern in diagnostic studies and implicitly or explicitly researchers use different threshold values as the criterion of scan positivity. We re-calculated the pooled results by imposing lower threshold values, which resulted in an increase in sensitivity (4%) and decrease in specificity (2%). This shows the importance of threshold value in the interpretation of 11C-acetate PET images. A lower threshold would be beneficial when higher sensitivity is desirable, e.g. in patients with PSA relapse but no evidence of disease on the anatomical imaging. However, this would invariably mean lower specificity and risk of false positive results, which can be problematic in some clinical scenarios: i.e. for determining the malignant or benign nature of a lesion detected on the anatomical imaging. In these situations a more stringent threshold value would be more prudent.

Localisation of Prostate Cancer Relapse: Local, Distant, and Lymph Nodes

Performance of 11C-acetate PET imaging in different locations (local vs distant or lymph nodes) is of utmost importance, as treatment planning is highly dependent on the location of relapse [2]. We extracted information on the performance of 11C-acetate for different locations of relapse from our included studies.

The performance of 11C-acetate imaging was better for distant and lymph node recurrence, as pooled sensitivity for detection of local recurrence was lower than for distant or lymph node recurrence (64.4 vs 81.6 and 81.5). This is most likely due to small tumoral tissue in the local recurrence cases, which cannot be detected by PET due to limited spatial resolution [41]. Pooled specificity for all locations was high (all >90%). However, false positive results were reported. For example, Wachter et al. [29] reported a false positive uptake in the thyroid and Sandblom et al. [28] reported three false positive results in lung cancer, oesophagitis, and lymphadenitis. In another study, Müller-Mattheis et al. [36] reported three out of seven positive lymph nodes as false positive results.

Comparison with Other Tracers

Several of the included studies used both 18F-FDG and 11C-acetate and invariably reported better results with 11C-acetate [16, 19, 20, 24, 31, 34, 35]. This better accuracy is attributed to excretion of 18F-FDG through the urinary system, which can obscure the tumoral lesions. The major metabolite of 11C-acetate (11C-carbone dioxide) is eliminated via the respiratory system. The mechanism of 11C-acetate uptake in prostate cancer lesions is also different from 18F-FDG, which results in higher uptake in the individual lesions [20].

Some studies also used 11C-acetate and choline PET imaging [21, 27, 33, 42] and reported comparable results with both tracers.

It should be mentioned that due to short half-life of 11C (20.4 min), use of 11C-acetate needs on-site synthesis, which is also a complicated and difficult task [43]. This can limit the availability of 11C-acetate imaging in prostate cancer.

Other Possible Applications

Wachter et al. [29] reported that 11C-acetate imaging resulted in a modified radiation field in six patients of their study. In another study Yu et al. [35] reported that 11C-acetate PET scanning was highly accurate for determining the response to treatment in patients with bone metastases. In a recent report by Gomez et al. [44], modification of RT treatment volumes, dose or both was required in three, one and three patients respectively due to 11C-acetate PET results. They also reported decreased SUV after successful RT. These possible applications warrant further evaluation in the future studies.

Haseebuddin et al. [39] reported on prognostic significance of 11C-acetate PET and found statistically significant higher recurrence in patients with PET-positive metastasis at any site. SUV maximum of the primary tumour also was higher in patients with recurrence (hazard ratio 1.11, although did not reach statistical significance). This is an interesting field of research and further studies are needed to evaluate the prognostic significance of 11C-acetate PET in prostate cancer.

Study Limitations

Publication bias

Publication bias is a major concern in all systematic reviews. Funnel plots as well as Egger's regression intercept method showed possible publication bias for both primary tumour and recurrence evaluation. The trim and fill method showed that adjustment of overall recurrence detection for possible publication bias would decrease the sensitivity (1.6%) and specificity (8.9%). This shows that publication bias, if present, can affect the result of the current meta-analysis and should be considered as an important limitation of the present study.

Quality of the included studies

The quality of the conducted studies on the application of 11C-acetate in prostate cancer was usually poor [45]. This is especially true for studies on re-staging at PSA relapse. The major shortcoming in the quality of the included studies in the present meta-analysis was poor and/or inconsistent gold standard. The researchers rarely provide histology results as the main gold standard method and usually relied on follow-up and conventional imaging (i.e. CT, bone scan, etc.). This is a major issue of the present study and our results should be interpreted with the knowledge of this limitation. High quality prospective studies with consecutive patient recruitment and applying the best gold standard (histology confirmation preferably) are definitely needed.

In conclusion, 11C-acetate PET imaging can be useful in patients with prostate cancer. This is especially true for evaluation of patients at PSA relapse, although the sensitivity is overall low. PSA values at relapse, primary treatment of the patients (surgery vs RT), and the instrument used for imaging (PET vs PET/CT) are related to the accuracy. For primary tumour evaluation (localisation of tumour in the prostate, differentiation of malignant from benign lesions, and detection of lymph node metastasis), 11C-acetate is of limited value due to low sensitivity and specificity. Due to the low quality of the included studies, the results should be interpreted with caution and further high-quality studies are needed to draw a more definite conclusion.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Conflict of Interest
  8. References
  • 1
    von Eschenbach A, Ho R, Murphy GP, Cunningham M, Lins N. American Cancer Society guideline for the early detection of prostate cancer: update 1997. CA Cancer J Clin 1997; 47: 261264
  • 2
    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 2002; 41: 569576
  • 3
    Dimitrakopoulou-Strauss A, Strauss LG. PET imaging of prostate cancer with 11C-acetate. J Nucl Med 2003; 44: 556558
  • 4
    Caroli P, Nanni C, Rubello D, Alavi A, Fanti S. Non-FDG PET in the practice of oncology. Indian J Cancer 2010; 47: 120125
  • 5
    Beresford MJ, Gillatt D, Benson RJ, Ajithkumar T. A systematic review of the role of imaging before salvage radiotherapy for post-prostatectomy biochemical recurrence. Clin Oncol (R Coll Radiol) 2010; 22: 4655
  • 6
    Sadeghi R, Gholami H, Zakavi SR, Kakhki VR, Horenblas S. Accuracy of 18F-FDG PET/CT for diagnosing inguinal lymph node involvement in penile squamous cell carcinoma: systematic review and meta-analysis of the literature. Clin Nucl Med 2012; 37: 436441
  • 7
    Grassi I, Nanni C, Allegri V et al. The clinical use of PET with 11C-acetate. Am J Nucl Med Mol Imaging 2012; 2: 3347
  • 8
    OCEBM Levels of Evidence Working Group. The Oxford Levels of Evidence 2. Oxford Centre for Evidence-Based Medicine. Available at: http://www.cebm.net/index.aspx?o=5653. Accessed June 2013
  • 9
    Devillé WL, Buntinx F, Bouter LM et al. Conducting systematic reviews of diagnostic studies: didactic guidelines. BMC Med Res Methodol 2002; 2: 9
  • 10
    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177188
  • 11
    Moses LE, Shapiro D, Littenberg B. Combining independent studies of a diagnostic test into a summary ROC curve: data-analytic approaches and some additional considerations. Stat Med 1993; 12: 12931316
  • 12
    Walter SD. Properties of the summary receiver operating characteristic (SROC) curve for diagnostic test data. Stat Med 2002; 21: 12371256
  • 13
    Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629634
  • 14
    Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000; 56: 455463
  • 15
    Zamora J, Abraira V, Muriel A, Khan K, Coomarasamy A. Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol 2006; 6: 31
  • 16
    Oyama N, Akino H, Kanamaru H et al. 11C-acetate PET imaging of prostate cancer. J Nucl Med 2002; 43: 181186
  • 17
    Kato T, Tsukamoto E, Kuge Y et al. Accumulation of [11C]acetate in normal prostate and benign prostatic hyperplasia: comparison with prostate cancer. Eur J Nucl Med Mol Imaging 2002; 29: 14921495
  • 18
    Kotzerke J, Volkmer BG, Neumaier B, Gschwend JE, Hautmann RE, Reske SN. Carbon-11 acetate positron emission tomography can detect local recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 2002; 29: 13801384
  • 19
    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 2003; 44: 549555
  • 20
    Fricke E, Machtens S, Hofmann M et al. Positron emission tomography with 11C-acetate and 18F-FDG in prostate cancer patients. Eur J Nucl Med Mol Imaging 2003; 30: 607611
  • 21
    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 2003; 42: 2530
  • 22
    Alavi S, Kurtaran A, Ilruby S, Wachter S, Malberger M, Djavan B. Multicenter evaluation of carbon-II acetate pet imaging in men with PSA progression following radical prostatectomy. Eur Urol Supp 2003; 2: 22
  • 23
    de Jong IJ, Pruim J, Jongen MMGJ, Elsinga PH, Mensink HJA, Vaalburg W. Visualization and quantification of uptake of 11C-acetate in prostate cancer and in benign prostatic hyperplasia with PET. Groningen University, The Netherlands, Thesis. 2003
  • 24
    Seltzer MA, Jahan SA, Dahlbom M et al. Combined metabolic imaging using C-11 acetate and FDG PET for the evaluation of patients with suspected recurrent prostate cancer. J Nucl Med 2003; 44: 132P
  • 25
    Manente P, Vicario G, Chierichetti F, Liessi G, Bissoli S. Preliminary experience with 11C-acetate and positron emission tomography (PET) in prostate cancer. J Clin Oncol 2005; 23: 422S
  • 26
    Albrecht S, Buchegger F, Soloviev D et al. (11)C-acetate PET in the early evaluation of prostate cancer recurrence. Eur J Nucl Med Mol Imaging 2007; 34: 185196
  • 27
    Vees H, Buchegger F, Albrecht S et al. 18F-choline and/or 11C-acetate positron emission tomography: detection of residual or progressive subclinical disease at very low prostate-specific antigen values (<1 ng/mL) after radical prostatectomy. BJU Int 2007; 99: 14151420
  • 28
    Sandblom G, Sorensen J, Lundin N, Haggman M, Malmstrom PU. Positron emission tomography with C11-acetate for tumor detection and localization in patients with prostate-specific antigen relapse after radical prostatectomy. Urology 2006; 67: 9961000
  • 29
    Wachter S, Tomek S, Kurtaran A et al. 11C-acetate positron emission tomography imaging and image fusion with computed tomography and magnetic resonance imaging in patients with recurrent prostate cancer. J Clin Oncol 2006; 24: 25132519
  • 30
    Schumacher D, Sorensen J, Brekkan E, Wassberg C, Malmstrom PU. The value of 11C-Acetate PET for lymph node staging in patients with newly diagnosed prostate cancer – results of a prospective study. Eur Urol Suppl 2009; 8: 319
  • 31
    Han KS, Cho KS, Joung JY et al. Localization of prostate cancer: a prospective intra-patient comparison study of MR imaging, fluorine 18-fluorodeoxyglucose PET/CT and carbon 11-Acetate PET/CT. Eur Urol Suppl 2009; 8: 355
  • 32
    Arenas JL, Canby-Hagino E. The efficacy of 11 carbon acetate PET scan in the staging and management of prostate cancer. J Urol 2009; 181: 781
  • 33
    Vees H, Buchegger F, Khan HG et al. Multiple Frame 18F-Fluorocholine or 11C-Acetate PET/CT Compared with Multi-modality MRI in Prostate Cancer Patients after Curative RT without Evidence of Relapse. Int J Rad Oncol Biol Physics 2009; 75: S349350
  • 34
    Oyama N, Tanase K, Ito H et al. 11C-acetate PET imaging of recurrent prostate cancer after radical prostatectomy detection of recurrent disease under PSA of 3.0 ng/mL. J Urol 2010; 183: e792
  • 35
    Yu EY, Muzi M, Hackenbracht JA et al. C11-acetate and F-18 FDG PET for men with prostate cancer bone metastases: relative findings and response to therapy. Clin Nucl Med 2011; 36: 192198
  • 36
    Müller-Mattheis V, Fahlbusch M, Hautzel H, Albers P. 11C-Acetate PET/CT imaging of prostate cancer: detection of recurrent disease in patients with PSA relapse following radical prostatectomy or radiotherapy. Eur Urol Suppl 2011; 10: 302
  • 37
    Jambor I, Borra R, Kemppainen J et al. Improved detection of localized prostate cancer using co-registered MRI and (11)C-acetate PET/CT. Eur J Radiol 2012; 81: 29662972
  • 38
    Mena E, Turkbey B, Mani H et al. 11C-Acetate PET/CT in localized prostate cancer: a study with MRI and histopathologic correlation. J Nucl Med 2012; 53: 538545
  • 39
    Haseebuddin M, Dehdashti F, Siegel BA et al. 11C-Acetate PET/CT before radical prostatectomy: nodal staging and treatment failure prediction. J Nucl Med 2013; 54: 699706
  • 40
    Sadeghi R, Tabasi KT, Bazaz SM et al. Sentinel node mapping in the prostate cancer. Meta-analysis. Nuklearmedizin 2011; 50: 107115
  • 41
    Picchio M, Briganti A, Fanti S et al. The role of choline positron emission tomography/computed tomography in the management of patients with prostate-specific antigen progression after radical treatment of prostate cancer. Eur Urol 2011; 59: 5160
  • 42
    Buchegger F, Garibotto V, Zilli T et al. First results of a comparative, prospective 11C-acetate and 18F-fluorocholine PET/CT study in prostate cancer patients relapsing after curative treatment with low PSA. Eur J Nucl Med Mol Imaging 2012; 39: S396
  • 43
    Fanti S, Nanni C, Lopci E et al. Imaging with (11)Carbon labelled PET tracers. Nucl Med Commun 2010; 31: 613616
  • 44
    Gomez JH, Blake M, Hernandez JO, Balam J, Teh BS. C11-Acetate positron emission tomography (PET) for prostate cancer patients undergoing radiation therapy. Int J Radiat Oncol Biol Phys 2012; 84: 371372
  • 45
    Morris MJ, Scher HI. (11)C-acetate PET imaging in prostate cancer. Eur J Nucl Med Mol Imaging 2007; 34: 181184