Treatment of patients with biochemically recurrent prostate cancer is guided by disease location and extent. Major guidelines recommend computed tomography (CT), magnetic resonance imaging (MRI), and/or bone scintigraphy at biochemical recurrence. However, these guidelines acknowledge limited sensitivity at low prostate-specific antigen (PSA) levels.^1-3 Novel positron emission tomography (PET) radiotracers promise to overcome this limitation, most recently with the approval of ¹⁸F-fluciclovine.^2,4,5 Among the various PET probes available, ⁶⁸gallium-labeled ligands of the prostate-specific membrane antigen (PSMA) were associated with unprecedented accuracy and effect on treatment in several meta-analyses of retrospective studies.^6-8 Although ⁶⁸Ga-PSMA-11 PET has been used extensively on a compassionate use basis and reported in numerous retrospective case series outside of the United States, prospective data are lacking.

Accurate staging in prostate cancer is key to planning initial treatments. In patients who undergo radical prostatectomy, the presence of pelvic lymph node metastases at time of surgery is correlated with biochemical failure.¹ However, conventional imaging used for staging, including computed tomography (CT), bone scan, and magnetic resonance imaging (MRI), is limited for the detection of metastatic disease, especially for nodal disease.² Therefore, improved detection of metastatic disease prior to definitive therapy is needed.

Somatostatin receptor (SSTR) PET has demonstrated a significant improvement over conventional imaging (CI) in patients with neuroendocrine tumors (NETs). SSTR PET should replace 111 In-pentetreotide scintigraphy (OctreoScan; Mallinckrodt) in all indications in which the latter is currently being used. These appropriate use criteria (AUC) are intended to aid referring medical practitioners in the appropriate use of SSTR PET for imaging of patients with NETs. The indications were evaluated in welldifferentiated NETs. Of the 12 clinical scenarios evaluated, 9 were graded as appropriate: initial staging after the histologic diagnosis of NET, evaluation of an unknown primary, evaluation of a mass suggestive of NET not amenable to endoscopic or percutaneous biopsy, staging of NET before planned surgery, monitoring of NET seen predominantly on SSTR PET, evaluation of patients with biochemical evidence and symptoms of a NET, evaluation of patients with biochemical evidence of a NET without evidence on CI or a prior histologic diagnosis, restaging at time of clinical or laboratory progression without progression on CI, and new indeterminate lesion on CI with unclear progression. Representatives from the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the American College of Radiology (ACR), the American Society of Clinical Oncology (ASCO), the North American Neuroendocrine Tumor Society (NANETS), the European Association of Nuclear Medicine (EANM), the Endocrine Society, the Society of Surgical Oncology, the National Comprehensive Cancer Network (NCCN), the American College of Physicians (ACP), the American Gastroenterological Association (AGA), and the World Conference on Interventional Oncology (WCIO) assembled under the auspices of an autonomous workgroup to develop the following AUC.

Background: ⁶⁸Ga-PSMA-11 PET is used to stage patients with prostate cancer. We performed an updated meta-analysis, which separates imaging at the time of diagnosis and that at the time of biochemical recurrence, and focuses on pathology correlation in both populations. Methods: We searched MEDLINE and EMBASE databases using the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) statement. Quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. A random effect model and a hierarchical summary receiver operating characteristic model was used to summarize the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for pelvic lymph nodes in initial staging compared to pathology at prostatectomy, and the PPV for lesions with pathologic correlation in those with biochemical recurrence. We also summarized the detection rate of ⁶⁸Ga-PSMA-11 in those with biochemical recurrence stratified by PSA at time of imaging. Results: The meta-regression analysis of ⁶⁸Ga-PSMA-11 in at initial staging demonstrated a sensitivity and specificity compared to nodal pathology at prostatectomy was 0.74 (0.51, 0.89), 0.96 (0.85, 0.99). At biochemical recurrence, the PPV was 0.99 (0.96, 1.00). The detection rate was 0.63 (0.55, 0.70) with a PSA less than 2.0, and 0.94 (0.91, 0.96) with a PSA greater than 2.0. Conclusion: ⁶⁸Ga-PSMA-11 performed well for the localization of metastatic prostate cancer at initial staging patients and at the time of biochemical recurrence.

Purpose: To evaluate the effect of androgen receptor (AR) inhibition on Prostate Specific Membrane Antigen (PSMA) uptake imaged using ⁶⁸Ga-PSMA-11 Positron Emission Tomography (PET) in a mouse xenograft model and in a patient with castration sensitive prostate cancer. Procedures: We imaged three groups of four mice bearing LNCaP-AR xenografts before and seven days after treatment with ARN-509, orchiectomy and control vehicle. Additionally, we imaged one patient with castration sensitive prostate cancer before and four weeks after treatment with androgen deprivation therapy (ADT). Uptake on pre- and post-treatment imaging was measured and compared. Results: PSMA uptake increased 1.5 to 2.0 fold in the xenograft mouse model after treatment with both orchiectomy and ARN-509, but not with vehicle. Patient imaging demonstrated a seven-fold increase in PSMA uptake after the initiation of ADT. 13 of 22 lesions in the imaged patient were only visualized on PSMA PET after treatment with ADT. Conclusion: Inhibition of the AR can increase PSMA expression in prostate cancer metastases and increase the number of lesions visualized using PSMA PET. The effects seen in cell and animal models can be recapitulated in humans. Further work needs to be done to better understand temporal changes of PSMA expression in order to leverage this effect for both improved diagnosis and therapy.