Localized Prostate Cancer
- Written by: Neal D. Shore, MD, FACS, and Michael S. Cookson, MD, MMHC
Currently, there is a global pandemic surrounding the spread of betacoronavirus SARS-CoV-2 leading to Coronavirus Disease 2019 (COVID-19). The rapid spread to all corners of the globe has had tremendous health and economic implications, including the appropriate allocation of healthcare resources. Considering that hospitals may be overwhelmed quickly given the need for a proportion of patients that require hospitalization with possible ventilator support, there is a necessity to decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. This includes reassessing the priority and implications of treatments, including prostate cancer screening.
- Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
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- Written by: Neal D. Shore, MD, FACS, Medical Director of the Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina, and Michael S. Cookson, MD, MMHC, Professor and Chairman, Department of Urology, Donald D. Albers Endowed Chair in Urology, Stephenson Cancer Center, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma
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- Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
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Imaging is often used to evaluate men with biochemical recurrence (BCR) of prostate cancer after definitive primary treatment (radical prostatectomy [RP] or radiotherapy [RT]). The goal of imaging is to identify the source of elevated or rising serum prostate-specific antigen (PSA) levels because subsequent management depends on disease location and extent.
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75. Treglia G, Ceriani L, Sadeghi R, Giovacchini G, Giovanella L. Relationship between prostate-specific antigen kinetics and detection rate of radiolabelled choline PET/CT in restaging prostate cancer patients: a meta-analysis. Clin Chem Lab Med. 2014;52:725–733.
76. Castellucci P, Ceci F, Graziani T, et al. Early biochemical relapse after radical prostatectomy: which prostate cancer patients may benefit from a restaging 11C-choline PET/CT scan before salvage radiation therapy? J Nucl Med. 2014;55:1424–1429.
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78. Nanni C, Zanoni L, Pultrone C, et al. 18F-FACBC (anti1-amino-3-18F-fluorocyclobutane1-carboxylic acid) versus 11C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging. 2016;43:1601–1610.
79. Bach-Gansmo T, Nanni C, Nieh PT, et al. Multisite experience of the safety, detection rate and diagnostic performance of fluciclovine (18F) positron emission tomography/computerized tomography imaging in the staging of biochemically recurrent prostate cancer. J Urol. 2017;197:676–683.
80. England JR, Paluch J, Ballas LK, Jadvar H. 18F-fluciclovine PET/CT detection of recurrent prostate carcinoma in patients with serum PSA # 1 ng/mL after definitive primary treatment. Clin Nucl Med. 2019;44:e128–e132.
81. Andriole GL, Kostakoglu L, Chau A, et al. The impact of positron emission tomography with 18F-fluciclovine on the treatment of biochemical recurrence of prostate cancer: results from the LOCATE trial. J Urol. 2019;201:322–331.
82. Akin-Akintayo OO, Jani AB, Odewole O, et al. Change in salvage radiotherapy management based on guidance with FACBC (fluciclovine) PET/CT in postprostatectomy recurrent prostate cancer. Clin Nucl Med. 2017;42:e22–e28.
83. Drug Dictionary NCI. Indium In 111 capromab pendetide. National Cancer Institute website. https://www.cancer.gov/publications/dictionaries/cancer-drug/ def/indium-in-111-capromab-pendetide. Accessed September 11, 2019.
84. Capromab pendetide. https://www.pharmacodia.com/yaodu/html/v1/biologics/ b4f1ec9f4b5c8207f8fc29522efe783d.html. Accessed September 11, 2019.
85. Thomas CT, Bradshaw PT, Pollock BH, et al. Indium-111-capromab pendetide radioimmunoscintigraphy and prognosis for durable biochemical response to salvage radiation therapy in men after failed prostatectomy. J Clin Oncol. 2003;21:1715–1721.
86. Pucar D, Sella T, Schöder H. The role of imaging in the detection of prostate cancer local recurrence after radiation therapy and surgery. Curr Opin Urol. 2008;18:87–97.
87. Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[18F]FACBC positron emission tomography-computerized tomography and 111In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol. 2014;191:1446–1453.
88. Schuster DM, Savir-Baruch B, Nieh PT, et al. Detection of recurrent prostate carcinoma with anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid PETCT and 111In-capromab pendetide SPECT/CT. Radiology. 2011;259:852–861.
89. BlueCross BlueShield of Tennessee Medical Policy Manual. Radioimmunoscintigraphy imaging (monoclonal antibody imaging) with Indium-111 capromab pendetide for prostate cancer. https://www.bcbst.com/mpmanual/Radioimmunoscintigraphy_ Imaging_Monoclonal_Antibody_Imaging_with_Indium-111_Capromab_Pendetide_for_Prostate_Cancer_.htm. Published November 10, 2007. Reviewed October 11, 2018. Accessed September 11, 2019.
90. BlueCross BlueShield of North Carolina. Corporate medical policy: monoclonal antibody imaging for prostate cancer. https://www.bluecrossnc.com/sites/ default/files/document/attachment/services/public/pdfs/medicalpolicy/monoclonal_ antibody_imaging_for_prostate_cancer.pdf. Published May 2011. Reviewed April 2018. Accessed September 11, 2019.
91. Aytu BioScience discounting PROSTASCINT (Cpromab Pendetide) Kit [letter]. April 2018. http://www.radiopharmaceuticals.info/uploads/7/6/8/7/76874929/ prostascint_discontinue_letter_april_2018_final.pdf. Accessed September 11, 2019.
92. Afshar-Oromieh A, Babich JW, Kratochwil C, et al. The rise of PSMA ligands for diagnosis and therapy of prostate cancer. J Nucl Med. 2016;57:79S–89S.
93. Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of hybrid 68Ga-PSMA ligand PET/CT in 248 patients with biochemical recurrence after radical prostatectomy. J Nucl Med. 2015;56:668–674.
94. Hope TA, Goodman JZ, Allen IE, Calais J, Fendler WP, Carroll PR. Metaanalysis of 68Ga-PSMA-11 PET accuracy for the detection of prostate cancer validated by histopathology. J Nucl Med. 2019;60:786–793.
95. Perera M, Papa N, Christidis D, et al. Sensitivity, specificity, and predictors of positive 68Ga-prostate-specific membrane antigen positron emission tomography in advanced prostate cancer: a systematic review and meta-analysis. Eur Urol. 2016;70:926–937.
96. Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective comparison of 18Ffluoromethylcholine versus 68Ga-PSMA PET/CT in prostate cancer patients who have rising PSA after curative treatment and are being considered for targeted therapy. J Nucl Med. 2015;56:1185–1190.
97. Afshar-Oromieh A, Zechmann CM, Malcher A, et al. Comparison of PET imaging with a 68Ga-labelled PSMA ligand and 18F-choline-based PET/CT for the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging. 2014;41:11–20.
98. Calais J, Ceci F, Eiber M, et al. 18F-fluciclovine PET-CT and 68Ga-PSMA-11 PET/CT in patients with early biochemical recurrence after prostatectomy: a prospective, single-centre, single-arm, comparative imaging trial. Lancet Oncol. 2019;9:1286–1294.
99. Lawhn-Heath C, Flavell RR, Behr SC, et al. Single-center prospective evaluation of 68Ga-PSMA-11 PET in biochemical recurrence of prostate cancer. AJR. 2019;213:266–274.
100. Fendler WP, Calais J, Eiber M, et al. Assessment of 68Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. JAMA Oncol. 2019;5:856–863.
101. Wu SY, Boreta L, Shinohara K, et al. Impact of staging 68Ga-PSMA-11 PET scans on radiation treatment plans in patients with prostate cancer. Urology. 2019;125:154–162.
102. Calais J, Fendler WP, Eiber M, et al. Impact of 68Ga-PSMA-11 PET/CT on the management of prostate cancer patients with biochemical recurrence. J Nucl Med. 2018;59:434–441.
103. Calais J, Czernin J, Cao M, et al. 68Ga-PSMA-11 PET/CT mapping of prostate cancer biochemical recurrence after radical prostatectomy in 270 patients with a PSA level of less than 1.0 ng/mL: impact on salvage radiotherapy planning. J Nucl Med. 2018;59:230–237.
104. Calais J, Czernin J, Fendler WP, Elashoff D, Nickols NG. Randomized prospective phase III trial of 68Ga-PSMA-11 PET/CT molecular imaging for prostate cancer salvage radiotherapy planning. BMC Cancer [PSMA-SRT]. 2019;19:18.
105. Sanchez-Crespo A. Comparison of gallium-68 and fluorine-18 imaging characteristics in positron emission tomography. Appl Radiat Isot. 2013;76:55– 62.
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Second, the use of transrectal ultrasound (TRUS) for prostate visualization and biopsy guidance became widespread. The use of TRUS allowed for direct visualization of the prostate, any of its anomalies, as well as the biopsy needle. Thus, TRUS-guided prostate biopsy became the gold standard approach to prostate cancer diagnosis.3 However, there are well-known limitations to TRUS-guided prostate biopsy including inherent random and systematic errors. Unless clear visible hypoechoic suspicious areas are seen in TRUS, sampling occurs by chance, and specific zones are under-sampled, including the anterior region and apex.4 Further, TRUS-guided systematic prostate biopsy can miss up to 20% of clinically significant prostate cancer, resulting in underdiagnosis and undertreatment.5 However, at the same time, TRUS-guided systematic prostate biopsy detects a relatively high percentage of clinically insignificant prostate cancer (Gleason grade group [GGG] 1), which may result in overtreatment.6
Thus, thirdly, multiparametric magnetic resonance has recently been evaluated for the identification of prostate lesions likely to be cancerous, as well as the guidance of prostate biopsy.
Initially, MRI was used as a staging test in patients with prostate cancer for assessment of direct extra-prostatic extension utilizing T2-weighted imaging. This approach was marked by significant variability in diagnostic performance, limited ability to detect microscopic disease and inability to localize the tumor within the gland itself.7 These factors limited the widespread adoption of MRI for local tumor staging. Indeed, to this data, TNM staging for prostate cancer relies on digital rectal examination rather than radiographic findings for local tumor staging.
However, multiparametric MRI, particularly with the addition of diffusion-weighted imaging has allowed for increasingly informative studies, including the visualization of tumors within the prostate. This has allowed for the use of mpMRI to guide prostate biopsy, either directly with in-bore biopsy or more commonly using a fusion device platform.8 When performed in the evaluation of patients with elevated prostate-specific antigen (PSA) levels with previous negative prostate biopsy, multi-parametric magnetic resonance imaging has been shown to identify clinically significant prostate cancers which would have been otherwise missed by routine systematic biopsy.9 A recent systematic review and meta-analysis from Kasivisvanathan and colleagues suggested that multi-parametric magnetic resonance imaging targeted biopsy detects more clinically significant prostate cancer than standard TRUS-guided systematic biopsy alone and requires fewer prostate cores to do so; that the question of whether to include systematic biopsy along with multi-parametric magnetic resonance imaging targeted biopsy remains controversial; and that the omission of the systematic biopsy risks missing the diagnosis of clinically significant disease in approximately 13% of men while the inclusion of systematic biopsy increases the likelihood of diagnosing clinically insignificant prostate cancer.10
The most recent European Association of Urology Prostate cancer guidelines conclude that, when at least one functional imaging technique is employed, mpMRI has good sensitivity for the detection and localization of clinically significant (Gleason Grade Group 2 or greater) prostate cancers6 with lower sensitivity for the detection of Gleason Grade Group 1 cancers, likely a beneficial characteristic. Potential limitations of the widespread use of a multi-parametric magnetic resonance imaging driven diagnostic pathway include only a moderate inter-reader reproducibility of multi-parametric magnetic resonance imaging, the lack of standardization of targeted biopsy, and cost-effectiveness concerns in certain jurisdictions.
Even more recently, high-resolution micro-ultrasound has emerged as a novel imaging modality for prostate cancer. High-resolution micro-ultrasound has a very fine resolution (approximately 70 µm) which allows for visualization of alterations in ductal anatomy and cellular density consistent with prostate tumors.11 In early experiences, high-resolution micro-ultrasound has demonstrated an ability to detect clinically significant cancers that were not apparent on either traditional TRUS or mpMRI.12 In contrast to mpMRI, high-resolution micro-ultrasound has the advantage of providing real-time imaging results, a finding that authors from the Cleveland Clinic demonstrated was associated with a relative increase in prostate cancer detection of 26.7%.12 Aggregate data from early clinical experience at multiple centers suggests that high-resolution micro-ultrasound has comparable or increased sensitivity for clinically significant prostate cancer compared with mpMRI and comparable or slightly reduced specificity.11
Distant staging – from radiographs to molecularly targeted imaging
While mpMRI has revolutionized imaging of the prostate and substantially changed the diagnostic algorithm for prostate cancer, perhaps even greater changes have occurred in the imaging for distant disease.
Initially, a radiographic diagnosis of bony prostate cancer metastasis was made on the basis of plain radiographs. However, bony metastases may be difficult to identify based on plain films as an extensive bone mineral loss (exceeding 30-50%) may be required before such changes are radiographically apparent.13 However, plain films remain useful for the immediate investigation of patients who present with bony pain and for the assessment of bony stability in those deemed at risk of pathologic fracture.
Following plain projectional radiography, skeletal scintigraphy was the next imaging modality widely adopted for the assessment of bony metastases in patients with prostate cancer. To date, it remains widely utilized and is currently recommended, along with abdominal and pelvic computed tomography, for the staging of patients according to many guideline bodies. Skeletal scintigraphy, when performed in patients with known cancer in the absence of bony pain, has a sensitivity of 86% and specificity of 81% for the detection of metastatic lesions.13 As with any imaging modality, these characteristics differ somewhat on the basis of the patient population being tested (i.e. the pre-test probability or population-based disease prevalence). Among patients with prostate cancer, PSA levels are predictive of the likelihood of a positive bone scan. Across a number of different cancers, Yang et al. found that bone scintigraphy had a specificity of 81.4% and sensitivity of 86.0%, on a per-patient basis, for the detection of bony metastases.14
Computed tomography has been utilized for the assessment of nodal metastatic disease, visceral disease, and bony metastasis. CT is highly sensitive for both osteoblastic tumors (such as prostate cancer) and osteolytic lesions in the cortical bone but is less sensitive in tumors that are restricted to the marrow space.13 As a result, CT is of relatively limited utility as a screening test for bony metastasis due to relatively low sensitivity (73%) despite excellent specificity (95%) – numbers based on a large scale meta-analysis from Yang and colleagues.14 For this reason, conventional staging recommendations for patients with prostate cancer include bony scintigraphy for the detection of bony lesions along with computed tomography for identification of nodal/visceral lesions and correlation of any bony lesions.15
In addition to its role in the local staging of the prostate and guidance of prostate biopsy, mpMRI may also assist with evaluation for distant metastatic disease. Routine pelvic/prostate MRI typically allows for assessment of local/regional nodal involvement including obturator and external iliac nodal chains. However, the high soft-tissue contrast and high spatial resolution afforded by MRI call also allow for the identification of bony metastasis in marrow spaces much early than would be apparent based on CT scan.14 Further, use of T1-weighted sequences and STIR sequences can allow for adequate assessment for bony metastasis without the need for intravenous contrast agents; use of MRI for staging does not require the use of ionizing radiation. Thus, abdominal/pelvic or whole-body MRI may be considered for the identification of distant metastatic disease. Additionally, MRI with contrast has become the imaging modality of choice for the evaluation of liver metastases.16 Thus, this approach may be particularly valuable in patients at a high risk of visceral metastatic disease.
Traditional positron emission tomography (PET) imaging utilizing fluorodeoxyglucose (FDG) is not typically effective in the initial diagnosis of prostate cancer metastasis owing to the relatively low metabolic activity associated with the disease. However, at least four other PET imaging approaches have been assessed and employed in patients with prostate cancer including 18F-NaF PET/CT, choline-based PET/CT, fluciclovine (Axumin®) PET/CT, and PSMA-targeted PET/CT.17 These modalities have been used in the staging of both primary and recurrent prostate cancer. While clearly improved compared to bony scintigraphy, the limitations are similar – namely, that sensitivity is highly dependent on PSA levels. However, choline-based PET/CT has demonstrated significantly higher sensitivity for the diagnosis of metastatic lesions at the time of biochemical recurrence compared to conventional imaging with a bone scan and computed tomography.17 However, compared to MRI, the benefits of choline-based PET/CT are less clear.18 MRI clearly outperformed choline-based PET/CT for the detection of local recurrence (36.1% vs 1.6%), while choline-PET/CT was superior for identification of lymph node metastasis and both were effective at identifying bony metastatic disease.19
Choline-based PET/CT is not widely available in the United States. However, fluciclovine PET/CT (also known as Axumin® PET/CT) which utilizes the proliferation of tumor cells for localization, is much more available. Fluciclovine (18F-FACBC; 1-amino-3-fluorine 18F-flurocyclobutane-1-carboxylic acid) is a synthetic amino acid analog with the advantage of negligible renal uptake and no activity in the urinary tract.18 Nevertheless, non-specific prostate uptake limits its utility in the identification of primary prostate tumors due to an inability to distinguish from benign prostatic inflammation. Instead, fluciclovine-PET/CT has proven efficacy in the detection of recurrent prostate cancer with biochemical recurrence following local therapy, with a sensitivity of 90% and specificity of 40% (higher in distant, 97%, and nodal disease, 55%, than locally).20 Compared to choline-PET/CT, fluciclovine-PET/CT demonstrated lower false-negatives and false-positive rates in patients with biochemical recurrence.21, 22
Finally, receptor-targeted PET imaging has recently been examined, most notably, PSMA-based PET/CT. PSMA is a transmembrane glycoprotein found on prostatic epithelium. The ratio of PSMA to its truncated isoform (PSM’) is proportional to tumor aggressivity. The most well examined PSMA based approach is 68Ga-PSMA-PET/CT. In patients with biochemical recurrence following radical prostatectomy, 68Ga-PSMA-PET/CT demonstrated superior detection rates of metastatic disease (56%) compared with fluciclovine-PET/CT (13%).23 This benefit was consistent in detecting pelvic nodal disease and extrapelvic disease. PSMA-based PET/CT demonstrated a particular benefit in the evaluation of patients with low absolute PSA levels. Further, 68Ga-PSMA-PET/CT appears to be superior to MRI in primary staging of patients prior to local therapy.24 Other radiotracers including 18F-DCFPyL and 177Lu-PSMA-617 have recently been examined in place of 68Ga-PSMA.25
Recent work has also assessed the role of PET/MRI, rather than PET/CT. This approach leverages the advantages of the sensitivity of receptor-targeted imaging and the spatial resolution of MRI.24
The evolution of imaging in prostate cancer has allowed a more nuanced understanding of the disease. Assessing the local tumor, both mpMRI and high-resolution micro-ultrasound allow for a more informed prostate biopsy which may assist in more accurate initial disease characterization26 as well as local staging. Ongoing advances in receptor-targeted PET imaging continue to refine the identification of metastatic disease. This has important implications for what we understand to be M0 and M1 prostate cancer. Whether early detection of metastatic disease utilizing these modalities translates into improvements in patient outcomes, or simply lead-time bias, remains to be assessed.
Published Date: March 19th, 2020
- Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
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