Clinical impact of PSMA PET/CT in primary prostate cancer compared to conventional nodal and distant staging: a retrospective single center study

Management strategies for primary prostate cancer, whether with curative or palliative intent, have their own morbidities and costs. Recently estimated costs of prostate cancer therapies in Australia were US$ 15 K–35 K per patient and US$ 270.9 M in total, with an expected increase of 42% in 2025 [1]. Imaging has a pivotal role in staging of and selecting the appropriate management strategy in men with primary prostate cancer. Bone scintigraphy (BS) with Technetium-99 m [^99mTc] labeled bisphosphonates has been the most widely used method for detecting bone metastases of PCa, based on visualizing the increased osteoblastic activity of bone metastases [2]. Due to its moderate sensitivity and specificity, BS frequently results in equivocal findings regarding the presence of bone metastases [3‐5]. Nonetheless, for primary staging of newly diagnosed PCa, BS is still recommended for distant staging, combined with cross-sectional abdominopelvic imaging for local and lymph node staging, in all high-risk patients [2].

After its clinical introduction in 2011, PET imaging with agents targeting the prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein that is highly overexpressed on most PCa cells, has shown increasing adoption. Its value for staging recurrent PCa has already been well established [6].

More recently, PSMA PET/CT imaging was evaluated as a potential tool for staging primary prostate cancer in men prior to curative treatment [7]. Specificity rates of 84–100% were reported by earlier studies [8‐11] and in a recent systematic review [12]. However, the sensitivity of PSMA PET/CT for the detection of lymph node metastases is moderate (33–91%), most likely due to the limitations in the spatial resolution to detect small (< 3 mm) lymph node tumour deposits in primary as well as recurrent prostate cancer [13]. Its performance with regard to distant metastases and impact on clinical management compared to conventional staging is less investigated.

In our institute, a Gallium-68 [⁶⁸Ga] labeled PSMA PET/CT was added to the conventional staging procedure in men with intermediate and high-risk PCa (predominant Gleason pattern 4 or higher, and/or cT3 or higher, and/or PSA blood level ≥ 20) from June 2016 onwards. The aim of the present study is to evaluate the impact of additional PSMA PET/CT on staging and clinical management of men evaluated for primary PCa compared with a conventional staging protocol.

In this study, the clinical impact of additional diagnostic information from PSMA PET/CT was compared with conventional staging in patients with intermediate and high-risk prostate cancer. A considerable impact on both staging and clinical management was found. Compared to conventional primary staging of PCa, PSMA PET/CT changed N stage in 33% and M stage in 36%, resulted in a net increase in the LoC of 9% for N status and of 20% for M status, and led to a treatment category change in 36%.

A growing number of studies compared PSMA PET/CT with conventional primary staging for primary PCa. Earlier studies found superior detection rates of PSMA PET/CT for bone metastases compared to BS in primary PCa patients [3, 4, 17]. Furthermore, PSMA PET/CT induced management changes were reported by Roach et al. in 21% of a larger cohort of primary PCa patients [18].

The recently published prospective multicentre proPSMA trial confirms the superior accuracy of PSMA PET/CT to conventional imaging (CT and bone scintigraphy) in assessing pelvic nodal and distant metastatic disease (92% vs 65%) in high-risk primary PCa [19]. Furthermore, equivocal findings were less (7% vs 23%) and PSMA PET/CT conferred more management changes (28% vs 15%). Also, when used as second-line imaging which is comparable to our study setting, PSMA PET/CT resulted in significant upstaging of nodal status compared to conventional imaging (23,3% vs. 8,8% positive) and management changed occurred in 27%.

The findings of our study are in line with abovementioned studies. In 33% of patients N stage was changed with information from PSMA PET/CT, mostly resulting in upstaging (23%). Although correctness of these findings could not be formally assessed in our study, the high reported specificity of PSMA PET/CT for nodal metastases in primary staging of PCa suggests that upstaging would be correct in most cases, warranting considerable changes in patient management, such as increasing the extent of the PLND or the radiotherapy field [8‐11, 20, 21].

PSMA PET/CT-induced treatment category changes in our study ranged from a conservative 13% (curative to palliative, or vice versa) to an optimistic 36% (any treatment category change). This is in line with abovementioned studies as well. Prostate cancer management is likely to be more and more patient-tailored and adjusted to staging information of imaging, such as tumour delineation in radiotherapy planning which may be signficantly influenced by PSMA PET/CT [21]. Findings that may not result in a considerable management change now, may do so in the future. The LoC in determining the correct N stage was considerably higher with PSMA PET/CT compared to conventional staging, though equivocal results remained in up to 6%. This is comparable with abovementioned studies as well. Further development of structured reporting criteria for negative and positive nodes may help to reduce the number of equivocal results and increase the LoC [15].

The major limitation of our study is the retrospective nature. Impact of PSMA PET/CT may be overestimated because patients may have been more likely to receive a PSMA PET/CT because of inconclusive findings on conventional imaging. Patients with overt metastases on BS probably are underrepresented because PSMA PET/CT may have been omitted due to lack of clinical consequences, and this may have overestimated staging and management impact of PSMA PET/CT as well. However, this reflects clinical practice as BS is cheaper and more readily available and may serve as an adequate first line M staging tool in patients with highly elevated PSA levels. Furthermore, a true gold standard (histopathology) lacks in most cases, especially for distant metastases. The final diagnosis is substantially influenced by the findings of the PSMA PET/CT itself, leading to incorporation bias and overestimating the accuracy of PSMA PET/CT. The management changes described here however represent clinical practice. Although predefined rules were followed, the setting of the smaller unblinded expert group may have influenced the results of the fictional restaging and subsequent preferred treatment. Finally, the proportion of contrast-enhanced CTs in this study was low. Although literature showed poor sensitivity for CT in determining N stage and no established role in determining M stage in primary PCa, the comparison of PSMA PET/CT with conventional staging in our study may have been limited [22].

Use of ADT at time of PSMA PET imaging is allowed according to EANM procedure guideline on 68Ga-PSMA PET/CT imaging [23], however tracer uptake and therefore PET staging results may be influenced by ADT [24]. As only five of 64 patients were undergoing hormonal therapy at time of PSMA PET, we do not think this has impacted our results.

The purpose of this study was not to assess the comparative accuracy of the conventional staging and the staging with PSMA PET/CT. Since histopathological confirmation of N status in the non-surgical treatment group lacked and confirmation of M status clinically was not feasible or did not have consequences, a true gold standard was not available. However, a high negative predictive value of PSMA PET/CT for M status is indicated by the 27 patients treated with RARP who reached biochemical disease-free status or were likely to have alternative sites of residual disease. Notably four of these patients were staged positive and two of them equivocal with conventional staging method. Thus, in addition to reported higher sensitivity of PSMA PET/CT for bone metastases compared to BS in primary staging of PCa [4], our data indicate a superior specificity of PSMA PET/CT compared to conventional staging.

Compared to conventional primary staging of PCa, PSMA PET/CT changes N stage in 33% and M stage in 36%, leading to treatment category change in 36%. BS was false-positive for distant metastases in 15–22% of cases. Findings of this study support the replacement of BS and CT by PSMA PET/CT in primary staging of PCa, but prospective analyses are needed to confirm a possible beneficial effect on survival outcome.