Background
68Ga-PSMA-HBED-CC (
68Ga-PSMA) positron emission tomography/computed tomography (PET/CT) has emerged as the gold standard in staging prostate cancer patients with biochemical persistence or recurrence after radical prostatectomy compared to conventional imaging like computed tomography (CT) or magnetic resonance imaging (MRI) [
1,
2] and choline PET/CT [
3]. PSMA PET/CT results in a modification of treatment e.g. addition of antiandrogen therapy (ADT), enlargement of the irradiated volume or even omission of radiotherapy in the event of advanced, metastatic disease in a remarkable high number of patients (33.8–76%) with biochemical persistence or recurrence [
4‐
10]. Unlike conventional imaging, PET with
68Ga-PSMA offers the unique possibility of visualising prostate cancer residual disease or recurrence at very low prostate-specific antigen (PSA) levels with 58.3% of PET-positive results found in a PSA range of 0.51–1.0 ng/ml [
11‐
16]. Data stemming from retrospective dose escalation studies in patients with biochemical recurrence after radical prostatectomy confirmed that a higher radiation dose is significantly associated with a risk reduction in biochemical failure [
17] and was not associated with a difference in acute grade 2 and 3 genitourinary or gastrointestinal toxicity in a single randomised study - SAKK 09/10 when irradiating the former prostate bed with 64 Gy vs. 70 Gy [
18]. Since the advent of PSMA PET/CT, dose escalation to macroscopic tumor residual disease or recurrence is now more precisely possible and is potentially associated with a further improvement of biochemical recurrence-free survival. Currently, there is paucity of data regarding outcome after PSMA PET/CT-based surgical [
19‐
21] or radiotherapeutic treatment [
22‐
27] in patients with persistent or recurrent prostate cancer. Since February 2014, offering PSMA PET/CT to all patients with recurrent or persistent prostate cancer after radical prostatectomy at our department, we evaluated the outcome following PSMA PET/CT-based radiotherapy.
Methods
Study population
In February 2014,
68Ga-PSMA PET/CT prior to radiotherapy was introduced at our department as the standard diagnostic staging tool routinely utilised in prostate cancer patients. A total of 176 consecutive patients underwent PSMA PET/CT prior to radiotherapy. 129/176 (73%) patients received PSMA PET/CT due to biochemical persistence (52%) or recurrence (48%) after radical prostatectomy without evidence of distant metastases (Table
1). 47/176 (27%) patients were excluded from the analysis: In 20/47 patients PSMA PET/CT was performed in the primary setting and in 27/47 patients distant metastatic disease was diagnosed. All patients provided written informed consent to undergo
68Ga-PSMA PET/CT. This retrospective analysis was performed in compliance with the principles of the Declaration of Helsinki and its subsequent amendments [
28] and was approved by the Ethics Committee of our Medical Faculty.
Table 1
Patients’ characteristics
N | 129 | 62 | 67 |
Median age | 72 (47–83) | 74 (50–83) | 70 (47–83) |
Tumor stage |
pT2 | 43 (33%) | 35 (57%) | 8 (12%) |
pT3a | 36 (28%) | 17 (27%) | 19 (28%) |
pT3b | 48 (37%) | 8 (13%) | 40 (60%) |
pT4 | 2 (2%) | 2 (3%) | – |
Nodal stage |
pN0 | 79 (61%) | 46 (74%) | 33 (49%) |
pN1 | 37 (29%) | 8 (13%) | 29 (43%) |
pNx/cN0 | 13 (10%) | 8 (13%) | 5 (8%) |
Positive surgical margins | 60 (47%) | 16 (26%) | 44 (66%) |
Gleason score |
6–7 | 70 (54%) | 44 (71%) | 26 (39%) |
8–9 | 59 (46%) | 18 (29%) | 41 (61%) |
Median PSA at RPE | 10.85 (2.37–190) | 8.55 (2.37–48) | 18.05 (3.99–190) |
Postoperative PSA | 0.12 (< 0.03–40.13) | < 0.03 | 0.47 (0.08–40.13) |
Months since RPE | 33 (2–192) | 61 (9–192) | 8 (2–94) |
Median PSA at PSMA PET/CT | 0.62 (0.13–40.13) | 0.44 (0.15–6.24) | 0.90 (0.13–40.13) |
Median PSA at PSMA PET/CT in PET positive pts | 1.09 (0.14–40.13) | 0.78 (0.27–6.24) | 1.6 (0.14–40.13) |
Median PSA at PSMA PET/CT in PET negative pts | 0.3 (0.13–3.24) | 0.3 (0.13–3.24) | 0.34 (0.13–1.33) |
PSMA PET/CT result |
Negative | 51 (39%) | 31 (50%) | 20 (30%) |
Fossa recurrence only | 24 (19%) | 16 (26%) | 8 (12%) |
Lymph node positive only | 42 (33%) | 12 (19%) | 30 (45%) |
Fossa and lymph node recurrence | 12 (9%) | 3 (5%) | 9 (13%) |
Treatment application and follow up
All patients received PSMA PET/CT as staging prior to radiotherapy. Treatment management following PSMA PET, e.g. initiation of ADT for PET-positive results, treatment of pelvic lymphatic pathways and simultaneous boost volumes to local recurrence or lymph node recurrence supplementary to the irradiation of former prostate was documented for each patient. Follow-up examination was first performed 3 months after irradiation and then every six to 12 months. Follow-up time was defined as the interval in months between radiotherapy and the last recorded PSA.
PSMA ligand and PET/CT imaging
PSMA-HBED-CC was radiolabelled with
68Ga
3+ 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. [
29].
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, Bayer Pharma AG, 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 (mean 205 megabecquerel (MBq)). Directly prior to the PET/CT scan, patients were implored to empty their bladders to minimise tracer accumulation.
Image interpretation
PET/CT was interpreted by a consensus read by one nuclear medicine physician and one radiologist. Location of lesions was each determined by CT. PET-positive lesions were visually identified by
68Ga-PSMA uptake 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. Local recurrence was identified by
68Ga-PSMA uptake and/or increased contrast enhancement in the prostate bed [
30].
Radiotherapy treatment
Planning CT was done in supine position. Patients were advised to have a full bladder and an empty rectum. All patients received radiotherapy with intensity modulated RT (IMRT) or volumetric arc therapy (VMAT) and image-guided RT (IGRT) techniques (2–5 times/week) using cone-beam CTs. Target delineation was performed according to the Radiation Therapy Oncology Group (RTOG) atlas for salvage prostate cancer. The clinical target volume (CTV) of the former prostate gland is defined superiorly as 5 mm above the inferior border of the vas deferens remnant, inferiorly as above the top of penile bulb, anteriorly by the pubic symphysis, posteriorly by the anterior rectum and laterally by the medial edge of the obturator internus muscle. Planning target volume (PTV) was derived by expanding the CTV by a 5–7 mm margin in all directions. Generally, an overall dose of 66 Gy with 2 Gy per fraction was applied to the prostate bed and 50.4 Gy with 1.8 Gy per fraction to the lymphatic pathways when PET-positive nodal involvement was detected. PET-positive pelvic lymph nodes were treated with a simultaneous-integrated boost (1.85–2.2 Gy per fraction). Likewise, a simultaneous integrated/sequential boost (2.0–2.14 Gy per fraction) was applied in case of local recurrence in PSMA PET/CT. The delineation of the gross tumor volume (GTV), i.e. local recurrence or suspicious lymph, nodes was based on 68Ga-PSMA uptake above background and increased contrast enhancement in the prostate bed and on increased short axis diameter, loss of fatty hilum, or increased contrast enhancement of the respective lymph nodes.
Statistical analysis
For statistical analysis, SPSS Statistics 24 (IBM, New York, USA) was used. Time to event data was calculated using the Kaplan-Meier method. Differences between subgroups were compared using log rank test with a p value of < 0.05 considered statistically significant. Uni- and multivariate logistic regression analysis was used to identify predictors for treatment response.
Discussion
PSMA PET/CT is currently the best available imaging technique to differentiate local relapse in the prostate bed, pelvic lymph node metastases or even metastatic disease in patients with biochemical persistence or recurrence [
31]. Particularly, in patients considered for salvage radiation treatment, PSMA PET/CT has a high detection rate of prostate cancer lesions outside the prostatic fossa [
15], corresponding to the number of men failing after salvage irradiation of the prostate fossa. Thus in 5%/19% of our patients treated due to biochemical failure, PSMA PET/CT revealed pelvic nodal involvement with/without local recurrence, respectively. As expected, patients with biochemical persistence being significantly more high-risk patients had a significantly higher rate of PET-positive pelvic lymph node metastases with/without local disease (13%/45%). This leads to a remarkable change in treatment e.g. the modification of radiation fields, dose escalation to macroscopic tumour lesions and initiation of ADT, as already extensively studied in current literature [
4‐
9].
Furthermore, PSMA PET/CT is especially sensitive in identifying tumour recurrence at PSA levels well below 1.0 ng/ml [
12], enabling radiotherapy initiation at PSA levels that are still considered curable [
32]. Currently, no general recommendation for a PSA cut-off prior to postoperative staging with PSMA PET/CT exists, although some data suggest a PSA of 0.83 ng/ml as an optimal cut-off value [
33]. In comparison, PET-positive findings were seen in our cohort at a slightly lower median PSA (0.78 ng/ml) in patients with biochemical recurrence vs. biochemical persistence (median PSA 1.6 ng/ml).
All patients with biochemical recurrence or persistence underwent PSMA PET/CT-based radiation treatment: absence of PET-positive disease resulted in irradiation of the prostate bed exclusively, whereas in the case of local recurrence a SIB was delivered. Additionally, presence of PET-positive pelvic lymph nodes resulted in irradiation of the pelvic basin with SIB to the involved nodes.
Extrapolated from data for pN+ patients treated with adjuvant radiotherapy and concurrent ADT [
34,
35], ADT was recommended for 2 years with evidence of PET-positive lesions. Although, 73 patients were started on ADT, about two-thirds discontinued prematurely after a median time of 5 (2–25) months due to patients’ preferences.
Based on a median follow-up of 20 months and an overall number of 129 patients, our analysis shows the high impact of PSMA PET/CT on oncologic outcome and is in accordance with the currently limited number of analyses on outcome after PSMA PET/CT-based radiotherapy in persistent or recurrent prostate cancer with mostly shorter follow-up [
22‐
26]: Our analysis shows that there is a high rate and long-lasting treatment response to irradiation based on pre-treatment PSMA PET/CT in patients with biochemical recurrence or persistence with 84% presenting with a PSA ≤ 0.2 ng/ml at a median follow-up of 20 months. When restricting the analysis to PET-positive patients without ADT at last follow-up (45 patients), the most challenging and interesting subgroup, 89% had a PSA ≤ 0.2 ng/ml. Splitting this subgroup further into patients with biochemical recurrence vs. persistence, the number of patients with PSA ≤ 0.2 ng/ml after a median follow-up of 20 months becomes even more divergent: 94% of patients with biochemical recurrence and evidence of PET-positive disease without ADT at last median follow up had a PSA level ≤ 0.1 ng/ml and ≤0.2 ng/ml vs. 82% of patients with biochemical persistence having a PSA ≤ 0.2 ng/ml (
p = 0.019; Fig.
2d). This mainly reflects the fact that men with biochemical recurrence in our cohort had significantly more local relapses within the prostate fossa compared to men with biochemical persistence with significantly more pelvic nodal involvement in PSMA PET/CT. Emmett et al. [
23] likewise reported on treatment outcome from PSMA PET/CT informed salvage radiation treatment in men with rising PSA following radical prostatectomy: based on a shorter median follow-up of 10.5 months, they also saw a high number of treatment response to radiotherapy (29/36 patients; 83%) when disease was confined to prostate fossa compared to patients with PET-positive nodal involvement (16/26 patients; 61%). Furthermore, the high number of 94% of PET-positive patients with biochemical recurrence having a PSA ≤ 0.1 ng/ml after 20 months in our cohort compares nicely to the analysis of Zschaeck et al. [
22] on 20 recurrent high-risk prostate cancer patients with a median PSA of 0.15 ng/ml after a median follow-up of 29 months.
Achieving a post-radiotherapy PSA nadir ≤0.1 ng/ml and radiotherapy indication (biochemical recurrence vs. persistence) were the only factors associated with a PSA ≤ 0.2 ng/ml at last follow-up in our cohort. This is in accordance with the recent data by Bartkowiak et al. [
36] demonstrating that men with undetectable post-radiotherapy PSA have lower rates of metastases and a better overall survival. Unlike the findings by Emmett et al. [
23] that PSMA PET result (negative or fossa recurrence only vs. PET-positive lymph nodes vs. distant metastases) is predictive of treatment response to salvage radiotherapy, we did not see any correlation between PSMA PET result (negative or fossa recurrence only vs. PET-positive lymph nodes) and biochemical recurrence-free survival. This is most likely to due to the fact, that we restricted our analysis to non-metastasised patients in contrast to the study by Emmett et al. which included patients with metastatic disease. Furthermore, contrary to data from literature showing a strong association between pre-RT PSA and progression-free survival [
32,
36], there was no such association between pre-RT PSA ≤/> 0.5 ng/ml and PSA ≤0.2 ng/ml at last follow-up in our cohort.
Our study has several limitations mainly as it is a retrospective study. Moreover, there was a low number of patients with biochemical recurrence that limits the statistical power of a multivariate analysis. Thus, a validation of our results within a larger cohort would be preferable.
Currently, PSMA PET/CT is the best diagnostic tool available for patients with rising PSA post-radical prostatectomy. Yet, it may still underestimate the true extent of disease in particular for the detection of small volume lymph nodes below 4 mm due to the inherent physical limitations of PET imaging [
1,
37] as well as for lesions close to the prostate fossa overshadowed by the SUV and radioactivity concentration within the bladder [
38,
39]. The implementation of novel 18F–labeled PSMA tracers may overcome this issue because of its low clearance via the urinary tract. Consequently, one third of our PET-negative patients, all treated with irradiation to the prostate fossa, failed biochemically at last follow-up. Since all data available consistently document that PSA control is significantly better when radiotherapy is commenced as early as possible [
32,
40,
41], it is nevertheless not justifiable to wait until PSA is in an optimal range or surpasses a cut-off for diagnostic assessment.