Advances in receptor targeted PET imaging continue to refine the identification of metastatic disease.
Radiographic imaging has played a key role in the diagnosis and staging of patients with prostate cancer for decades. Transrectal ultrasound and multiparametric magnetic resonance imaging are important in diagnosis and local staging of the primary tumor, while axial imaging, bone scintigraphy, and molecularly targeted positron emission tomography contribute for distant staging. However, only a few decades ago, none of these approaches was widely utilized. Although multiparametric MRI (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, radiographic diagnosis of bony prostate cancer metastasis was made on the basis of plain radiographs; however, this is a very insensitive approach, requiring extensive bone mineral loss (exceeding 30% to 50%) before changes are radiographically apparent.1
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.1 As with any imaging modality, these characteristics differ somewhat on the basis of the patient population being tested (eg, the pretest probability or population-based disease prevalence). Among patients with prostate cancer, prostate-specific antigen (PSA) levels are predictive of the likelihood of 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.2
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.1 As a result, CT is of relatively limited utility as a screening test for bony metastasis due to a relatively low sensitivity (73%) despite excellent specificity (95%)–numbers based on a large scale meta-analysis from Yang and colleagues.2 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.3
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 could also allow for the identification of bony metastasis in marrow spaces much early than would be apparent based on CT scan.2 Further, use of T1-weighted sequences and short tau inversion recovery (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.4 This approach may be particularly valuable in patients at high risk of visceral metastatic disease.
In recent years, there has been growing interest in the use of positron emission tomography (PET) imaging to diagnose prostate cancer. While traditional PET/CT utilizing fluorodeoxyglucose is not typically effective, however, at least 4 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.5 These modalities have been used in staging of both primary and recurrent prostate cancer. Although clearly improved compared with bony scintigraphy, the limitations are similar, in that sensitivity is highly dependent on PSA levels. 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 analogue with the advantage of negligible renal uptake and no activity in the urinary tract.6 Nevertheless, nonspecific prostate uptake limits its utility in 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).7 Compared with choline-PET/CT, fluciclovine-PET/CT demonstrated lower false negative and false positive rates in patients with biochemical recurrence.8,9
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 has demonstrated superior detection rates of metastatic disease (56%) compared with fluciclovine-PET/CT (13%).10,11 This benefit was consistent in detecting pelvic nodal disease and extrapelvic disease. PSMA-based PET/CT demonstrated 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.12
Most recently, the proPSMA trial compared the utility of 68Ga-PSMA-PET/CT with conventional imaging with CT and bone scan in a multicenter, 2-arm randomized controlled trial among men with histologically confirmed prostate cancer who were being considered for curative intent radical prostatectomy or radiotherapy.13 Patients were randomized to the conventional or PSMA-based staging, with crossover for those with fewer than 3 sites of unequivocal metastatic disease. Among 300 randomized patients, 295 of whom had assessment of the reference standard, PSMA PET-CT had a 27% absolute greater area under the receiver operating curve for accuracy compared with conventional imaging (95% CI 23-31): 92% (95% CI 88% to 95%) versus 65% (60% to 69%). Conventional imaging had both a lower sensitivity (38% versus 85%) and also a lower specificity (91% versus 98%). Further, equivocal findings were more common in men undergoing conventional imaging (23%) compared with those undergoing PSMA PET-CT (7%).
Prior to treatment, the results of conventional imaging studies resulted in treatment change for 23 men (15%, 95% CI 10-22) while the results of PSMA PET-CT resulted in treatment change for 41 (28%, 95% CI 21-36). These changes included both a transition from curative intent to palliative intent treatment in 20 patients (14%) and also a change in treatment approach in 22 (14%). These data demonstrate the clinical utility of utilizing PSMA PET-CT in this clinical space.
Finally, conventional imaging was associated with a higher radiation dose (19.2 mSv compared with 8.4 mSv; absolute difference 10.9 mSv, 95% CI 9.8-12.0 mSv0). PSMA PET-CT was not associated with any adverse events, and reporter agreement was high for both nodal (κ 0.87, 95% CI 0.81-0.94) and distant metastatic disease (κ 0.88, 95% confidence interval 0.94-0.92).
Although 68Ga-PSMA is the best studied and most well-known radiotracer utilized in this disease space, there are, as of October 2019, at least 25 different radiotracers under evaluation, based on studies registered at ClinicalTrials.gov.14 Among 104 studies at the time, 18F-DCFPyL and 177Lu-PSMA-617 were the most commonly used after 68Ga-PSMA.14
Recent work also has 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.12
The evolution of imaging in prostate cancer has allowed a more nuanced understanding of the disease. 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.
Wallis is a fellow in urologic oncology at Vanderbilt University Medical Center, Nashville, Tennessee.
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2. Yang HL, Liu T, Wang XM, et al. Diagnosis of bone metastases: a meta-analysis comparing 18FDG PET, CT, MRI and bone scintigraphy. Eur Radiol. 2011;21(12):2604-2617. doi:10.1007/s00330-011-2221-4
3. Network NCC. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer - Version 1.2019. 2019.
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5. Li R, Ravizzini GC, Gorin MA, et al. The use of PET/CT in prostate cancer. Prostate Cancer Prostatic Dis. 2018;21(1):4-21. doi:10.1038/s41391-017-0007-8
6. Rayn KN, Elnabawi YA, Sheth N. Clinical implications of PET/CT in prostate cancer management. Transl Androl Urol. 2018;7(5):844-854. doi:10.21037/tau.2018.08.26
7. Schuster DM, Nieh PT, Jani AB, et al. Anti-3-[(18)F]FACBC positron emission tomography-computerized tomography and (111)In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol. 2014;191(5):1446-1453. doi:10.1016/j.juro.2013.10.065
8. Wondergem M, van der Zant FM, van der Ploeg T, et al. A literature review of 18F-fluoride PET/CT and 18F-choline or 11C-choline PET/CT for detection of bone metastases in patients with prostate cancer. Nucl Med Commun. 2013;34(10):935-945. doi:10.1097/MNM.0b013e328364918a
9. Nanni C, Zanoni L, Pultrone C, et al. (18)F-FACBC (anti1-amino-3-(18)F-fluorocyclobutane-1-carboxylic acid) versus (11)C-choline PET/CT in prostate cancer relapse: results of a prospective trial. Eur J Nucl Med Mol Imaging. 2016;43(9):1601-10. doi:10.1007/s00259-016-3329-1
10. 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;20(9):1286-1294. doi:10.1016/S1470-2045(19)30415-2
11. Calais J, Fendler WP, Herrmann K, et al. Comparison of 68Ga-PSMA-11 and 18F-Fluciclovine PET/CT in a case series of 10 patients with prostate cancer recurrence. J Nucl Med. 2018;59(5):789-794. doi:10.2967/jnumed.117.203257
12. Eiber M, Weirich G, Holzapfel K, et al. Simultaneous 68Ga-PSMA HBED-CC PET/MRI improves the localization of primary prostate cancer. Eur Urol. 2016;70(5):829-836. doi:10.1016/j.eururo.2015.12.053
13. Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020;395(10231):1208-1216. doi:10.1016/S0140-6736(20)30314-7
14. Zippel C, Ronski SC, Bohnet-Joschko S, et al. Current status of PSMA-radiotracers for prostate cancer: data analysis of prospective trials listed on ClinicalTrials.gov. Pharmaceuticals (Basel) 2020;13(1). doi:10.3390/ph13010012
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