Our study has demonstrated a clinically significant impact on the management of patients with high-risk prostate cancer and BCR, imaged using 68Ga-THP-PSMA PET-CT.
Primary staging in high-risk prostate cancer
In our series of patients undergoing 68Ga-THP-PSMA PET-CT for primary staging, a management change (compared with the decision made in an MDM using standard diagnostic techniques) was noted in 12 of the 50 patients (24%). Roach et al. evaluated a comparable cohort of 108 patients scanned for primary staging and reported a 21% management change .
We noted a higher number of management changes in patients with PSA < 20 μg/L (34.6%) compared with patients with PSA > 20 μg/L (12.5%). This implies that at high PSA levels, conventional staging with MRI, bone scan and/or CT can detect nodal or metastatic disease, but at lower PSA levels, 68Ga-THP-PSMA PET-CT has greater sensitivity and management impact. We did not find a difference in management changes between patients with Gleason score < 8 and > 8.
Perera et al. analysed 16 studies involving 1309 patients who underwent a 68Ga-PSMA PET-CT (most used 68Ga-HBED-CC-PSMA, some did not mention the specific ligand), of which 40% of scans were positive for patients undergoing primary staging (95% CI 19–64%) . Four studies were evaluated for the predictive ability of PSMA PET-CT (scan positivity compared with histology), demonstrating a sensitivity of 80% and specificity of 97%.
Lymph node evaluation is integral to primary staging and there is a need for imaging which provides more sensitive detection in high-risk prostate cancer. Current practice regarding lymphadenectomy is reliant on pre-operative models using PSA levels, Gleason score and T-stage to dictate surgical planning .
Whilst our aim was not to specifically measure the accuracy of nodal detection, 68Ga-THP-PSMA PET-CT identified lymph nodes in 8/50 patients (16%). In 2 patients, identification of lymphadenopathy led to a management change: one to RARP with a unilateral PLND (histologically positive node) and one to radiotherapy and hormones instead of RARP.
A number of studies have evaluated the sensitivity and specificity of 68Ga-HBED-CC-PSMA PET-CT for lymph node detection. Sensitivity is reported as between 33.3–65.9% and specificity 98.9–100% [21, 22]. Budäus et al. reported that 68Ga-PSMA PET-CT scans identified 4 of 12 patients (33.3%) as node positive. In 8 patients with histologically confirmed lymph nodes, 68Ga-PSMA PET-CT was negative, giving a false-negative value of 66.7%.
Current EAU guidelines recognise that PLND are associated with worse peri- and postoperative outcomes, whilst a direct therapeutic effect is still not evident from the current literature. Thus, it is not our routine practice to offer surgery and lymph node dissection to patients with pathological nodes on imaging. A recent review of UK practice in 2017 demonstrated that most radical prostatectomies are performed for patients with Gleason grade group 2 and 3 disease (intermediate risk). Lymph node dissection rates were similar across all grade groups ranging from 13–15% .
In our cohort, 68Ga-THP-PSMA PET-CT detected 7 patients with metastatic disease at primary presentation (3 M1a and 4 M1b), which was greater than that identified by conventional imaging alone. Treatment choice did change as a result of these findings in 4/7 patients (57%).
In our BCR group undergoing 68Ga-THP-PSMA PET-CT, clinical management changed in 23 of the 68 patients (34%), with 59% of scans demonstrating positivity. In 23 scans, disease recurrence was identified locally (prostate or prostate bed), 23 in lymph nodes and in 9, metastatic disease was seen. In those where there was a management change, 10 patients were upstaged (42%) and 2 downstaged (8.3%), and in 12 scans (50%), staging was concordant with that of conventional imaging, but additional information relevant to treatment planning was identified.
Roach et al. in Australia and Afaq et al. in the UK have shown 62% and 39% change in management intent, respectively, in the BCR setting, with the use of 68Ga-HBED-CC-PSMA [17, 18]. Roach et al. have conducted the largest prospective multicentre study of 323 patients evaluating management intent. They evaluated all patients undergoing imaging for BCR, with a detectable PSA but negative conventional imaging. Overall clinical intent changed in 51% of patients following results of PSMA PET-CT. 68Ga-HBED-CC-PSMA PET-CT detected additional local disease in 27% of patients, nodes in 39% and metastatic disease in 16%.
The systematic review by Han et al., evaluating management changes following 68Ga-HBED-CC-PSMA PET, was performed for BCR in 11 studies . The proportion undergoing RT increased from 56 to 61%, typically with an increase in dose or target volume. There was an increase in patients undergoing salvage surgery from 1 to 7%, which included performing pelvic lymph node dissection (in our group, this decreased from 10.2 to 5.9%). The number of patients undergoing systemic treatment decreased from 26 to 12% (in our cohort, it increased from 5.9 to 10.2%). ADT was initially planned in 144 patients but was only commenced in 52 patients after 68Ga-HBED-CC-PSMA (in our group, planned in 28% and decreased to 25%). The proportion of patients with no treatment decision or on surveillance decreased from 14 to 11% (we report an increase from 29.4 to 38%). In addition, we report a small decrease in numbers undergoing radiotherapy (from 26.4 to 21%).
At PSA levels of 1.0 μg/L and above, we noted higher rates of management change (0% < 0.5 μg/L, 23% 0.5–1 μg/L, 46% 1–2 μg/L). Higher scan positivity and change in management rates were also seen in patients with short PSAdt < 6 months (56% vs 45.7% and 36.0% vs 25.7%, respectively). Similarly, those with higher Gleason scores > 8 had higher scan positivity rates (78.9% vs 51.2%) but broadly similar changes in management (36.8% vs 30.2%).
Fendler et al. using 68Ga-HBED-CC-PSMA PET-CT reported a detection rate of 75% in BCR. There was a significant increase in detection rate across PSA ranges, 38% for < 0.5 ng/mL, 57% for 0.5–< 1 ng/mL and 84% for 1.0 ng/mL . There were 8 cases where the PET findings were reported as negative but histology confirmed prostate cancer.
Similar trends were identified in a retrospective series by Ceci et al. regarding factors which correlated with 68Ga-HBED-CC-PSMA PET-CT detection in patients presenting with BCR .
68Ga-HBED-CC-PSMA PET-CT was positive in 23 of 39 patients (59 %) with PSA < 2 μg/L. These results are consistent with data recently reported by Afshar-Oromieh et al. who reported scan positivity rates with 68Ga-HBED-CC-PSMA PET-CT of 61.1% in 90 patients with PSA < 2 μg/L . PSA kinetics were evaluated, reporting that 68Ga-HBED-CC-PSMA PET-CT was positive in 85% of patients with low PSA values and short PSAdt, but in only 18.7% of patients with low PSA and long PSAdt. For Perera et al. in the BCR cohort, 68Ga-HBED-CC-PSMA PET positivity increased as serum PSA rose. For those with a PSA < 0.2 μg/L, the detection rate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and > 2.0ug/L PSA values, respectively . A similar trend was demonstrated with PSAdt, with a PSMA positivity of 92% for those with a PSAdt < 6 months and 64% for those ≥ 6 months. The authors again recognise the significant heterogeneity between the groups analysed.
Several studies have determined that the clinical detection rate was dependent on the PSA level, with Derlin et al. reporting rates as high as 94.1% for PSA > 10 μg/L, 54.5% for PSA 1–2 μg/L and 20% below 0.5 μg/L . Afaq et al., using 68Ga-HBED-CC-PSMA, reported an overall scan positive rate of 15.8% (PSA 0.2–0.5 μg/L), 33% (PSA 0.5–1 μg/L), 20% (PSA 1–2 μg/L) and 84.6% (PSA 2–5 μg/L) .
The difference in management change and scan positivity rates between these studies and ours might be explained by differences in prospective versus retrospective methodology, referral patterns and decision-making between Australian, European and UK practice. The data from Afaq et al., a UK study in the same city, is more comparable with ours and hence the closer values for management impact .
Whilst previous studies have reported higher detection rates with other PSMA ligands, 68Ga-THP-PSMA demonstrated reasonable detection rates in patients with BCR and PSA levels ≥ 1 μg/L. Potential explanations for the lower detection rates at very low PSA levels using this ligand compared with 68Ga-HBED-CC-PSMA include different use of ADT between studies which alters PSMA expression, faster renal clearance of THP compared with HBED and potential lower affinity of 68Ga-THP-PSMA. No comparisons have been performed to determine if this impacts on diagnostic accuracy or management.
68Ga-THP-PSMA can be labelled to Good Manufacturing Practice criteria in 5 min at room temperature as a single-step technique and has a potential practical and cost advantage over other 68Ga-labelled PSMA radiopharmaceuticals. Hofman et al., Young et al. and Derlin et al. have evaluated this ligand for its safety and bio-distribution, whole-body radiation dose, plasma clearance and correlation of uptake with tumour PSMA expression on histopathology [14, 15]. They demonstrated that 68Ga-THP-PSMA had lower background uptake in salivary glands, liver and spleen than 68Ga-HBED-CC-PSMA. Metastatic lesions were equally identified on both HBED-PSMA and THP-PSMA-PET scans. 68Ga-THP-PSMA provides a similar effective dose to that published for 68Ga-HBED-CC-PSMA (2.07 × 10−2 mSv/MBq).
This is a single-centre study and may not reflect practice in other units where diagnostic and treatment guidelines may differ. Nevertheless, the results reflect practice in a busy tertiary referral centre with a large surgical and oncological prostate cancer service. Management decisions were made in a multidisciplinary fashion for a consecutive cohort of patients. The study reports intended management and did not take into account actual treatment, which may on occasion differ from planned due to patient comorbidities or other patient-related factors. Not all of the PET-positive finding scans were validated by another procedure such as histological analysis of lymph nodes or visceral lesions (not always feasible) or conventional imaging.