Since the invention of the radiotracer Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] and its clinical introduction for PET imaging at our institute in May 2011, this highly promising method (68Ga-PSMA-ligand PET/CT) has rapidly spread. The first clinical experiences led to the assumption that 68Ga-PSMA-ligand PET/CT could be a significant step forward in the diagnosis of recurrent PCa [18–20, 26]. This imaging modality is based on the observation that almost all adenocarcinomas of the prostate gland express PSMA to which Glu-NH-CO-NH-Lys-(Ahx)-[68Ga(HBED-CC)] is able to bind with very high affinity [28, 29]. The aim of this evaluation was to assess 319 patients who were referred to our hospital for 68Ga-PSMA-ligand PET/CT from the first clinical implementation of this method in May 2011 until January 2014.
Overall, 82.8 % of the patients presented with at least one lesion characteristic for PCa in 68Ga-PSMA-ligand PET/CT. This rate is slightly lower compared to our previous reports [19, 20]. A possible explanation is that our previous studies were conducted in the initial phase of imaging with this novel method and that after 68Ga-PSMA-ligand PET/CT became increasingly better known, more challenging cases with negative alternative imaging results and low PSA values were referred to our hospital.
In the multivariate analysis a strong association was detected between a pathological 68Ga-PSMA-ligand PET/CT and the PSA level. This result was expected as an increase in PSA levels usually indicates progressive disease. However, as demonstrated by Fig. 3, a continuous increase in PSA level does not automatically correlate with an increase in tumor detection. In general the question remains why not more patients show a pathologic 68Ga-PSMA-ligand PET/CT although according to literature almost all prostatic adenocarcinomas express PSMA [28, 29]. Possible reasons could be the individual tumor heterogeneity, a dedifferentiation of PCa leading to a decoupling of tumor mass and PSA level, absent or very low PSMA expression of some tumors (e.g. neuroendocrine PCa), tumors adjacent to the urinary bladder, small tumour size below the spatial resolution of the PET scanner or the stage of technology of the PET scanner. With regard to the latter aspect we believe for example that new scanners with time of flight (TOF) technology enable more sensitive tumour detection.
In the most challenging cohort (patients with PSA <0.2 ng/ml) GSC was significantly higher in the group with pathological 68Ga-PSMA-ligand PET/CT compared to the group without pathological 68Ga-PSMA-ligand PET/CT. However, with regard to all patients analysed in this evaluation, the multivariate analysis did not show a relevant association between a positive 68Ga-PSMA-ligand PET/CT and GSC 7, 8 or 9–10 compared to a low GSC of 5–6. This result is contrary to our expectations: in the literature, a positive correlation between higher GSC and PSMA expression has been demonstrated in preclinical studies [30–32]. The sole explanation we have at this stage is that the small cohort of patients with GSC 5–6 causes substantial variability in the statistical analysis. We consider GSC as an important variable in both imaging and therapy with PSMA ligands. Further studies focusing on this topic are eagerly awaited.
The multivariate analysis also did not demonstrate a relevant association between a positive 68Ga-PSMA-ligand PET/CT and the five defined PSA DTs. At this stage, we assume that there is no significant correlation between proliferation index and PSMA expression of the tumours.
Patients with an ADT at the time of 68Ga-PSMA-ligand PET/CT more frequently showed a positive PET scan compared to patients without such treatment. One explanation for this result could be that patients with advanced disease are more often referred to ADT. However, this theory needs to be investigated in more detail as many cases exist in which ADT is started at low PSA values. We believe that the time to start ADT depends on many variables such as patients’ demands, preferences/experience of physicians, PSA DT, etc. In addition, ADT usually leads to a reduction of PSA levels and can also reduce the tumour size [33, 34]. Both have the potential to negatively influence the detection rate in imaging modalities. Another explanation for our findings could be that the PSMA expression is apparently differentially regulated by androgens. In previous preclinical studies, PSMA expression was downregulated by androgen therapy and upregulated by antiandrogen therapy [35–37]. This counterintuitive behaviour is not yet fully understood and more studies are eagerly awaited to investigate the influence of ADT on both diagnosis and therapy with PSMA ligands.
A noticeable but nonsignificant positive association was also detected between a positive 68Ga-PSMA-ligand PET/CT and lower amounts of injected radioactivity. However, according to our experience in routine clinical practice, tracer activities of more than 100–120 MBq lead to improved image quality while especially amounts less than 60–70 MBq cause the opposite. At this stage, our sole explanation for this unexpected finding is statistical variability. We do not believe that higher radioactivity amounts lead to any adverse molecular interaction as all injections contained 2 nmol PSMA ligand.
The analysis of SUV values within the manifestations of PCa demonstrate that uptake of 68Ga-PSMA-HBED-CC is high in primary tumours as well as in local relapses and all types of metastases. This result confirms our previous evaluation in which we could demonstrate that the total uptake of PCa lesions as well as tumour contrast are significantly higher compared to choline PET/CT . However, as shown in the aforementioned evaluation, it has to be considered that lymph node metastases usually present with the highest contrast, followed by bone metastases, local relapses and soft tissue metastases.
We assume that virtually all patients referred to our hospital had recurrent disease or persistent primary tumour and that our cohort did not include true-negative cases. Therefore, calculating patient-based specificity, NPV and PPV is not possible as described in the “Materials and methods” section. However, with regard to a lesion-based analysis, it is apparent that 68Ga-PSMA-HBED-CC is able to detect PCa with good sensitivity and excellent specificity (Table 3). Only 1 local relapse in 1 patient and 29 lymph node metastases in 3 other patients were false-negative. With regard to two of the latter patients (patients 34 and 37 in Table 3), PET-positive lymph nodes led to lymph node dissection of the pelvis where additional small lymph node metastases were found. These PET-negative lymph nodes were located in the same region as the PET-positive lymph nodes and had therefore no negative influence on the therapy procedure. We assume that the mentioned metastases were not detected by 68Ga-PSMA-ligand PET/CT due to a small size and low PSMA expression. However, with the exception of the above-mentioned PET-negative metastases in four different patients, all other lesions (n = 416) were true-positive or true-negative. This result demonstrates that 68Ga-PSMA-HBED-CC is highly specific for PCa. However, theoretically an expression of PSMA within inflammatory lesions can exist, although it is considered to be rare .
Overall, the histology results need to be interpreted with caution, e.g. cases with different numbers of lymph node metastases usually cause a bias. In addition, there was no standardized protocol to investigate PET-positive lesions. Calculating patient-based values of specificity, NPV and PPV is therefore not reasonable as mentioned before. The most important message of the histology results is that 68Ga-PSMA-HBED-CC is highly specific for PCa. At this stage, we suggest that accumulations of 68Ga-PSMA-HBED-CC in lesions outside the prostate gland have to be regarded as PCa-specific until proven otherwise. In addition, we suggest that specification of a cut-off SUV for malignant or benign tissue is not reasonable for lesions outside of the prostate gland. On the other hand, for lesions within the prostate gland, calculation of such cut-off SUVs can possibly help to distinguish different GSC or tumour and inflammatory tissue. However, such cut-offs cannot be provided by this evaluation as a sufficient number of benign tissues need to be analysed. Stereotactic biopsy studies are underway to provide more data.
Among the 116 patients who were available for follow-up, 50 (40 %) were treated locally after 68Ga-PSMA-ligand PET/CT and therefore delayed systemic therapy due to the results of the 68Ga-PSMA-ligand PET/CT. We believe that such patients who can delay systemic therapy have a greater potential for improved quality of life. Systemic therapies usually present with significant side effects and the therapeutic effect is frequently temporary. It also has to be considered that patients who present with locally accessible tumours have theoretically a better chance to be cured of their disease. However, long-term studies are necessary to evaluate the impact of 68Ga-PSMA-ligand PET/CT on the overall survival time and quality of life of PCa patients.
In this evaluation we could also demonstrate that a sour excretion stimulus does not reduce the high physiological radiotracer uptake of the salivary glands. We therefore assume that such a stimulus would not help to reduce radiation-related side effects of therapy with radiolabelled PSMA ligands.
Our retrospective analysis shows typical limitations compared to prospective studies: biased patient referrals and thereby possibly biased treatments and follow-up as well. However, we believe that our data reflect the daily clinical routine and that every centre which conducts 68Ga-PSMA-ligand PET/CT faces similar conditions. Our results and messages therefore can help to better understand PSMA imaging until more data are available in the future.
This evaluation investigated the diagnostic value of PET/CT imaging with the new 68Ga-labelled PSMA ligand HBED-CC (68Ga-DKFZ-PSMA-11) in the diagnosis of PCa. 68Ga-PSMA-ligand PET/CT 1 h p.i. can detect PCa in a high percentage of patients with suspected cancer (82.8 %). In addition, the tracer is highly specific for PCa: histological analysis demonstrated that accumulation of 68Ga-PSMA-HBED-CC in lesions correlates with manifestations of PCa in virtually all cases and false-positive lesions could not be detected. Detection of PCa is improved at higher PSA levels. Also, ADT had a significantly positive influence on tumour detection rate, which, however, has to be interpreted with caution. However, no association was found between a positive PET/CT and faster PSA DTs as well as GSC 7, 8 or 9–10 compared to a low GSC of 5–6. Amongst all patients who were available for follow-up after 68Ga-PSMA-ligand PET/CT, 40 % could be treated locally with resulting delayed systemic therapy. We could also demonstrate that an excretion stimulus using vitamin C does not lead to a reduction of the physiologically high 68Ga-PSMA-HBED-CC uptake in salivary glands. With regard to possible therapy of metastatic PCa with radiolabelled PSMA ligands, we therefore assume that such an excretion stimulus would not help to reduce radiation-based off-target effects to the salivary glands.