Detection level and pattern of positive lesions using PSMA PET/CT for staging prior to radiation therapy

⁶⁸Ga-PSMA PET/CT has been routinely offered to patients for prostate cancer staging before radiotherapy in our clinic (February 2014–August 2016). A total of 129 patients consecutively received ⁶⁸Ga-PSMA PET/CT prior to radiotherapy in different clinical scenarios: 20 patients at initial diagnosis (mostly high-risk patients with suspected extra-prostatic manifestations), 60 with biochemical persistence after radical prostatectomy and 49 with biochemical relapse (Table 1). All patients gave written informed consent to undergo ⁶⁸Ga-PSMA PET/CT. This retrospective analysis is in compliance with the principles of the Declaration of Helsinki and its subsequent amendments [21] and was approved by the Ethics Committee of the LMU Medical Faculty .

PSMA-HBED-CC was radiolabelled with ⁶⁸Ga³⁺ from a ⁶⁸Ge/⁶⁸Ga generator system (GalliaPharm^®, Eckert & Ziegler AG, Berlin, Germany) using an automated synthesis module (GRP, Scintomics GmbH, Munich, Germany) and pre-packed cassettes (ABX GmbH, Radeberg, Germany) as described previously for a different PSMA ligand by Weineisen et al. [22]. ⁶⁸Ga-PSMA PET/CT images extending from the base of the skull to the mid-thigh were acquired. PET/CT scan was obtained with intravenous injection of iodine-containing contrast agent (Ultravist 300, Schering, Berlin, Germany; or Imeron 300, Bracco, Konstanz; 2.5 mL/s; in portal venous phase) 60 min after almost simultaneous intravenous administration of 20 mg furosemide and ⁶⁸Ga-PSMA (median 189 megabecquerel (MBq), range 87–293). Directly prior to the PET/CT scan, patients were asked to empty their bladder to minimise tracer accumulation.

PET/CT was interpreted by a consensus read of one nuclear medicine physician and one radiologist. Location of lesions was each determined by CT. PET-positive lesions were identified by ⁶⁸Ga-PSMA uptake visually above background and not associated with the physiologic uptake. CT-positive nodes were defined by increased short axis diameter, loss of fatty hilum, or increased contrast enhancement. Bone metastases were detected by suspicious sclerotic lesions, visceral metastases by suspicious hypodense or hyperdense lesions in the respective organ. Based on PET/CT images and reports, stage according to PET or CT was documented separately by one nuclear medicine physician and one radiation oncologist [23].

Demographic and tumour characteristics were analysed. The association between positive ⁶⁸Ga-PSMA PET/CT findings and possibly interacting variables, like androgen deprivation therapy (ADT) at the time of PET/CT, amount of injected tracer, PSA-level, PSA doubling time, T−/N-category and Gleason score was assessed by univariate and multivariate logistic regression analysis. P values <0.05 were considered statistically significant. PSA before PET/CT was classified in eight steps (≤ 0.2 ng/ml – > 20 ng/ml). Gleason score was grouped in six different classes (GS 5/6, GS 7a, GS 7b, GS 8, GS 9 and GS 10), T-category in four (T1 – T4) and N-category in three classes (N0, N1, Nx). Injected tracer amount was evaluated as multiples of 100 MBq. Patients after radical prostatectomy were classified by PSA doubling time ≤ vs. > 10 months. PET/CT positive findings (primary tumour/local recurrence, lymph node and distant metastases) are presented separately according to the respective treatment indication prior to radiotherapy. The detection rate of residual tumour, recurrence or newly diagnosed disease comparing PET/CT to CT exclusively as well as change in radiotherapy management was analysed by Fisher’s test.

Patients with pathological radiotracer uptake (n = 92; Table 2) had a median PSA of 1.90 ng/ml (range 0.14–150.0), a PSA doubling time of mainly ≤10 months (77.8%), mainly a T3 N0 prostate cancer, a predominant GS 9 (29.3%) and ongoing ADT at time of PET in 12 patients. They were injected with a mean activity of 191.96 MBq ⁶⁸Ga-PSMA-HBED-CC (range 87–293) and were mainly high-risk patients (81.5%). Patients without pathological findings (n = 37; Table 2) had a median PSA of 0.30 ng/ml (range 0.13–3.24), a PSA doubling time of mainly ≤10 months (67.6%), mainly a T3 N0 prostate cancer and a predominant GS 7b. Mean activity of ⁶⁸Ga-PSMA-HBED-CC radiotracer was 186.78 MBq (range 94–293) in PET-negative patients with patients being mostly high-risk patients (75.7%) and two patients having ongoing ADT at the time of PET scan. In the univariate analysis (Table 3) no significant difference was found between PET-positive and PET-negative patients regarding the use of ADT at time of PET (p = 0.222), the injected amount of ⁶⁸Ga-PSMA-HBED-CC (p = 0.590), the PSA doubling time ≤/> 10 months (p = 0.517), GS (p = 0.285) and T- (p = 0.982) and N-category (p = 0.987). Concerning PSA before PET, a significant difference was found (p < 0.001). In the multivariate analysis, the significant association between a PET-positive result and PSA level a time of PET persisted (p = 0.002). Figures 1 and 2 demonstrate the probability of pathological ⁶⁸Ga-PSMA PET/CT depending on PSA level at time of PET/CT and GS. There is an almost linear increase of PET-positive result with rising PSA level: Patients with PSA ≤ 0.2 ng/ml had a detection rate of 33.3%, patients with PSA 0.21 ≤ 0.5 ng/ml a rate of 41.2% and patients with PSA 0.51 ≤ 1.0 ng/ml a rate of 69.2%.

Prior to definitive radiotherapy, ⁶⁸Ga-PSMA PET/CT showed suspicious lesions within the prostate gland in 90% of patients and suspicious pelvic lymph nodes and/or distant metastases in 20%/10% of the patients, respectively. ⁶⁸Ga-PSMA PET/CT had a high detection rate of prostate cancer recurrence outside the prostatic fossa in patients being considered for salvage radiotherapy: 22.4% of patients had PET-positive pelvic lymph nodes and 4.1% distant metastases. Both patients with distant metastases had also local recurrence exclusively without evidence of pelvic lymph node metastases. In patients considered for salvage radiotherapy with a PSA < 0.5 ng/ml (25 patients), ⁶⁸Ga-PSMA PET/CT detected in 16.0% local recurrences within the prostatic fossa and in 20.0% PET-positive pelvic lymph nodes. In patients with postoperatively biochemical persistence, PET/CT revealed a high number of lymph node metastases (58.3%), distant metastases (23.3%) and macroscopic residual tumour (21.7%). Seventeen of 60 patients with persistent PSA after radical prostatectomy had a pre-PSMA PET/CT PSA <0.5 ng/ml. Of these patients, there was one patient (5.9%) with macroscopic residual tumour, 7 patients with pelvic lymph node metastases (41.2%) and 1 patient with distant metastases (5.9%). The single patient with bone metastases had pelvic lymph node involvement as well. Figure 3 shows a lesion based analysis of PET-positive local recurrence/primary tumour, PET-positive lymph node and distant metastases according to sub-grouping of patients and contains additional information on simultaneous involvement of local recurrent tumour/primary tumour, lymph node metastases and/or distant metastases. ⁶⁸Ga-PSMA PET/CT as medical imaging modality had a significantly higher diagnostic value in the detection of suspicious lesions within the prostate/prostatic fossa (38% vs. 10.1%; p < 0.05), of suspicious pelvic lymph nodes (38.8% vs. 15.5%; p < 0.05) and distant metastases (14.0% vs. 5.4%; p < 0.05) compared to the contrast enhanced CT scan acquired during PET/CT imaging. This resulted in a modification of radiotherapy treatment in 56.6% of patients by e.g. enlarged target volumes or simultaneously integrated boost volumes. Figure 4 demonstrates the integration of ⁶⁸Ga-PSMA PET/CT images into radiation therapy planning in three patients.