Prostate cancer is the leading cause of cancer for men in the United States followed by skin cancer. The American Cancer Society estimates that this year in the US, there will be approximately 248,530 new cases of prostate cancer and approximately 34,130 deaths. [1]

Conventional imaging modalities, such as computed tomography (CT), bone scintigraphy, and magnetic resonance imaging (MRI) are currently used for the initial staging and detection of prostate cancer recurrence, however, these methods are limited looking at morphological changes only and, particularly lesions that are less than 1 cm in size and in patients with low prostate-specific antigen (PSA) levels (<20 ng/mL).[2][3] Consequently, these modalities limit utility in staging pelvic lymph nodes, low sensitivity for metastatic disease, and limited accuracy for low PSA.

The need for a novel type of imaging
The drawbacks of these modalities highlight the need for a novel type of imaging that is both safe and effective. 68Ga PSMA-11 is a radioactive diagnostic agent indicated for use with positron emission tomography (PET) for the detection of prostate cancer around the body by identifying the biological marker, Prostate-specific membrane antigen (PSMA). PSMA despite the name is not actually limited to only prostate cancers, but it is highly overexpressed in 95% of prostate cancer cells. [4]

68Ga PSMA-11 is the first FDA-approved PSMA–targeted PET imaging agent, with institutional approvals granted to the University of California, Los Angeles, and the University of California, San Francisco. Telix Pharmaceuticals is awaiting an FDA decision for the commercial use of its investigational product Illuccix® (TLX591-CDx) a kit for the preparation of 68Ga PSMA-11 before year-end. Submissions for marketing authorization for Illuccix® are also under review in 16 other countries, including Australia, Canada, and Europe.

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Clinical Studies
In a review of 49 studies evaluating 3,097 patients with primary prostate cancer and 23 studies evaluating 1,225 patients with biochemically recurrent (BCR) prostate cancer, 68Ga PSMA-11 has been shown to have higher specificity and sensitivity compared to conventional imaging in prostate cancer staging. Leading research in this area includes a study evaluating 300 patients in 10 centers across Australia, Hofman et al., compared 68Ga PSMA-11 PET/CT to the conventional imaging combination of CT and bone scan in the diagnosis and TNM staging for primary prostate cancer.

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This pivotal work found that 68Ga PSMA-11 PET/CT had a higher sensitivity (85% vs 38%) and specificity (98% vs 91%) than the combination of CT and bone scan, respectively. [5] Similarly, a recent prospective Phase 3 study by Hope et al who was one of the innovators of the product at UCLA, evaluated 764 patients with intermediate to high-risk prostate cancer with biopsy-proven prostate cancer who were suitable for prostatectomy and pelvic lymph node dissection. In this patient population, 68Ga PSMA-11 PET was found to have a sensitivity and specificity in the detection of pelvic lymph node metastasis. [6]  In a further study evaluating 144 patients with primary prostate cancer, Donato et al., found that 68Ga PSMA-11 PET/CT had a higher sensitivity for the detection of index lesions (90.1%) compared to multiparametric MRI (83.1%).

This study also found that 68Ga PSMA-11 PET/CT detected more clinically significant prostate cancer compared to multiparametric MRI (sensitivity, 94.9% vs 86.0%, respectively; P = 0.017). [7] Lastly, in yet another prospective trial evaluating 108 patients for primary staging, 68Ga PSMA-11 PET/CT was found to detect additional lymph node metastases and bone metastases in 25% and 6% of patients, respectively, leading to a change in clinical management in 21% of patients. [8]

68Ga PSMA-11 has consistently been shown to have a high detection rate at low PSA levels in BCR prostate cancer. Key studies in this area include Rauscher et al., who evaluated 68Ga PSMA-11 PET/CT for its detection rate in 272 consecutive patients with BCR prostate cancer, and found 68Ga PSMA-11 PET/CT to have a detection rate of 55% in patients with very low (0.2-0.5 ng/mL) PSA and 74% in patients with low (>0.5-1.0 ng/mL) PSA. [9]

In a retrospective analysis of 66 consecutive patients, Kranzbuhler et al., evaluated 68Ga PSMA-11 PET/MRI for its detection rate in patients with BCR prostate cancer with low PSA levels and found that PSMA-positive lesions were detected in 38.5% of patients with PSA <0.2 ng/mL and in 65% of patients with PSA ranging from 0.2 to 0.5 ng/mL. [10] In the PSMA-BCR study evaluating patients with BCR prostate cancer, 91% of the evaluable patients receiving 68Ga PSMA-11 PET were found to be true positive in one or more regions against the composite reference standard of either histopathology, serial serum PSA, or imaging (bone scintigraphy, CT, or MRI).[11]

Optimal treatment
The additional accuracy in staging shown with 68Ga PSMA-11 can result in changes to clinical management in patients with prostate cancer and lead to optimal treatment decisions. This is possible through the potential of 68Ga PSMA-11 to help identify disease more accurately than conventional imaging thus giving patients the best treatment option for their stage of the disease… 68Ga PSMA-11 has shown to be well tolerated  in patients who have undergone imaging with the agent, and is reported to have lower radiation exposure compared to conventional imaging.[5][6]

Economic analyses
Economic analyses have shown that 68Ga PSMA-11 can be a cost-effective alternative to conventional imaging. In a study evaluating 30 patients for the cost-effectiveness of 68Ga PSMA-11 PET/MRI for staging BCR prostate cancer, Gordon et al., found that 68Ga PSMA-11 PET/MRI was expected to cost an average of $39,426 and produce 7.48 life-years compared to an average of $44,667 and 7.41 life-years in usual care. [12] In a cost-effectiveness analysis of the Hofman et al. proPSMA study, 68Ga PSMA-11 PET/CT was found to have a lower estimated cost per scan compared to conventional imaging ($886 vs $1040).[13]. These studies have found that 68Ga PSMA-11 is cost-effective in comparison to usual care due to overall reduced costs and increased accuracy in staging, leading to the avoidance of unnecessary costs.

Guidelines
The clinical evidence supporting the use of 68Ga PSMA-11 in the initial staging and recurrence of prostate cancer in place of conventional imaging compelled the National Comprehensive Cancer Network (NCCN) Guidelines® to include 68Ga PSMA-11 in its recent update on September 10, 2021, and provide guidance on its use. In agreement, SNMMI recently updated its Appropriate Use Criteria (AUC) on September 15, 2021, to include 68Ga PSMA-11 for PSMA-PET imaging. The purpose of the AUC is to guide referring and imaging physicians to use PSMA PET imaging agents appropriately, the SNMMI, the American College of Nuclear Medicine (ACNM), the American Urological Association (AUA), the Australia and New Zealand Society of Nuclear Medicine (ANZSNM), and the American Society of Clinical Oncology (ASCO), worked collaboratively to develop criteria for the appropriate use of this new imaging technology[14]14.

The new guidelines conclude: “because of the increased sensitivity and specificity of PSMA-PET tracers for detecting micro-metastatic disease compared to conventional imaging (CT, MRI) at both initial staging and BCR, the Panel does not feel that conventional imaging is a necessary prerequisite to PSMA-PET and that PSMA-PET/CT or PSMA-PET/MRI can serve as an equally effective, if not more effective front-line imaging tool for these patients” [15]

68Ga PSMA-11 offers greater sensitivity and specificity compared to conventional imaging modalities and can result in clinical management changes for patients with primary and recurrent prostate cancer. 68Ga-PSMA-11 has also shown the potential to be a viable economic alternative to conventional imaging in the staging of prostate cancer.

Clinical trials
PSMA PET Imaging of Recurrent Prostate Cancer – NCT03204123

References
[1] Key Statistics for Prostate Cancer Online Last accessed October 9, 2021.
[2] Gupta M, Choudhury PS, Hazarika D, Rawal S: A Comparative Study of (68)Gallium-Prostate Specific Membrane Antigen Positron Emission Tomography-Computed Tomography and Magnetic Resonance Imaging for Lymph Node Staging in High Risk Prostate Cancer Patients: An Initial Experience. World J Nucl Med 2017, 16(3):186-191.
[3] Chen M, Zhang Q, Zhang C, Zhou YH, Zhao X, Fu Y, Gao J, Zhang B, Wang F, Qiu X et al: Comparison of (68)Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) and multi-parametric magnetic resonance imaging (MRI) in the evaluation of tumor extension of primary prostate cancer. Transl Androl Urol 2020, 9(2):382-390.
[4] Lenzo NP, Meyrick D, Turner JH: Review of Gallium-68 PSMA PET/CT Imaging in the Management of Prostate Cancer. Diagnostics (Basel) 2018, 8(1).
[5] Hofman MS, Lawrentschuk N, Francis RJ, Tang C, Vela I, Thomas P, Rutherford N, Martin JM, Frydenberg M, Shakher R et al: Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomized, multicentre study. Lancet 2020, 395(10231):1208-1216.
[6] Hope TA, Eiber M, Armstrong WR, Juarez R, Murthy V et al: Diagnostic Accuracy of 68Ga-PSMA-11 PET for Pelvic Nodal Metastasis Detection Prior to Radical Prostatectomy and Pelvic Lymph Node Dissection. JAMA Oncol. doi:10.1001/jamaoncol.2021.3771. September 16, 2021
[7] Donato P, Morton A, Yaxley J, Ranasinghe S, Teloken PE, Kyle S, Coughlin G, Esler R, Dunglison N, Gardiner RA et al: (68)Ga-PSMA PET/CT better characterises localised prostate cancer after MRI and transperineal prostate biopsy: Is (68)Ga-PSMA PET/CT guided biopsy the future? Eur J Nucl Med Mol Imaging 2020, 47(8):1843-1851.
[8] Roach PJ, Francis R, Emmett L, Hsiao E, Kneebone A, Hruby G, Eade T, Nguyen QA, Thompson BD, Cusick T et al: The Impact of (68)Ga-PSMA PET/CT on Management Intent in Prostate Cancer: Results of an Australian Prospective Multicenter Study. J Nucl Med 2018, 59(1):82-88.
[9] Rauscher I, Duwel C, Haller B, Rischpler C, Heck MM, Gschwend JE, Schwaiger M, Maurer T, Eiber M: Efficacy, Predictive Factors, and Prediction Nomograms for (68)Ga-labeled Prostate-specific Membrane Antigen-ligand Positron-emission Tomography/Computed Tomography in Early Biochemical Recurrent Prostate Cancer After Radical Prostatectomy. Eur Urol 2018, 73(5):656-661.
[10] Kranzbuhler B, Muller J, Becker AS, Garcia Schuler HI, Muehlematter U, Fankhauser CD, Kedzia S, Guckenberger M, Kaufmann PA, Eberli D et al: Detection Rate and Localization of Prostate Cancer Recurrence Using (68)Ga-PSMA-11 PET/MRI in Patients with Low PSA Values </= 0.5 ng/mL. J Nucl Med 2020, 61(2):194-201.
[11] Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, Nguyen HG, Reiter RE, Rettig MB, Okamoto S et al: Assessment of 68Ga-PSMA-11 PET Accuracy in Localizing Recurrent Prostate Cancer: A Prospective Single-Arm Clinical Trial. JAMA Oncol 2019, 5(6):856-863.
[12] Gordon LG, Elliott TM, Joshi A, Williams ED, Vela I: Exploratory cost-effectiveness analysis of (68)Gallium-PSMA PET/MRI-based imaging in patients with biochemical recurrence of prostate cancer. Clin Exp Metastasis 2020, 37(2):305-312.
[13] de Feria Cardet RE, Hofman MS, Segard T, Yim J, Williams S, Francis RJ, Frydenberg M, Lawrentschuk N, Murphy DG, De Abreu Lourenco R: Is Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography Imaging Cost-effective in Prostate Cancer: An Analysis Informed by the proPSMA Trial. Eur Urol 2021, 79(3):413-418.
[14] Jadvar H CJ, Fanti S, Feng F, Greene KL, Gulley JL, Hofman M, Koontz BF, Lin DW, Morris MJ, Rowe SP, Royce TJ, Salami S, Savir-Baruch B, Srinivas S, Hope TA: Appropriate Use Criteria for Prostate-Specific Membrane Antigen PET Imaging. SNMMI 2021:1-38.
[15]Schaeffer E; Srinivas S; Antonarakis ES; Armstrong AJ; Cheng HH; D’Amico AV; Davis BJ; Desai N; Dorff T; Eastham JA; Farrington TA GXG: NCCN Guidelines: Prostate Cancer, Version 1.2022. Natl Compr Canc Netw 2021, 19(2):134-143.

Featured image: Paper with prostate cancer and light blue ribbon. Photo courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission.

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