RECOMMENDATIONS FOR THE EARLY IDENTIFICATION OF METASTATIC DISEASE

Imaging Methods for Early Detection of Metastatic Disease

Current methods for the initial detection of bone metastases may be suboptimal,and strategies for the early identification of metastases in patients with prostate cancer have been recommended by the Radiographic Assessments for Detection of Advanced Recurrence Group (RADAR), and Canadian Urological Association (CUA)-Canadian Uro Oncology Group (CUOG).The 2025 Canadian Urological Association (CUA)-Canadian Uro Oncology Group (CUOG) guideline on the management of CRPC includes recommendations on detection of metastases and imaging in untreated patients

(Figure 8)

. For patients who progress on androgen deprivation therapy (ADT) without evidence of distant metastases, screening for bone metastases with bone scans and monitoring for lymph node and visceral metastases/progression with imaging of the abdomen/pelvis and chest is suggested.

Figure 8. Canadian guideline recommendations on detection of metastases

Rapid PSADT ( High risk for developing metastases earlier	Slower PSADT (>10 months)
Imaging should be performed every 3-6 months	Screening should be performed every 6-12 months

^{Adapted from Saad F}^{et al.}²⁰²⁵

Imaging techniques most commonly used include nuclear bone scans and abdominal/pelvic computed tomograph (CT) and chest X-ray. The role of positron-emission tomography (PET), such as prostate specific membrane antigen (PSMA)-PET are still unclear and the benefits unknown. When considering cost effectiveness, the RADAR Group recommended conventional bone scintigraphy using technetium 99 (^99mTc) and abdomen/pelvis/chest computed tomography (CT) as the imaging modalities for initial testing.

Other novel imaging modalities are available (

Table 1

), and the RADAR group suggested that plain radiography, magnetic resonance imaging (MRI), and 18F-Sodium Fluoride positron emission tomography/CT (NaF PET/CT) should be conducted at the physician’s discretion when necessary, as they might be needed to clarify equivocal lesions. PET/CT scans using tracers, such as 18F-NaF, show sensitivity and specificity values superior to bone scintigraphy (Table 1
) and are frequently incorporated into guidelines.

Table 1. Available Imaging Technologies

Imaging Test	Estimated Sensitivity (%)	Estimated Specificity (%)
99mTc28	78	48
F–NaF PET/CT	100	97
MRI	95	90
CT	74	56
PSMA-PET	98	96

PSMA: prostate-specific membrane antigen.

The Use of ALP and PSA Is an Effective Tool for Predicting Risk of Bone Metastatic Disease

Bone alkaline phosphatase (ALP) in combination with PSA can be an effective marker for predicting the risk of developing bone metastatic disease. Multivariate analyses from a study to identify predictors of bone metastatic disease in 203 individuals with asymptomatic, treatment-naive prostate cancer identified ALP and PSA as being independent predictors of bone metastases

(Table 2)

. The combination of elevated ALP and PSA (in which patients with either elevated PSA [>20 ng/mL] OR elevated ALP were considered as positive) had the best screening value for the detection of bone metastases, with a sensitivity of 98.2% and a specificity of 48.6%. The risk factors identified in this study and the recommendations provided by the RADAR group may be used to detect the onset of bone metastases in asymptomatic patients.

Monitor Key Bone-Related Parameters as Prognostic Factors for Overall Survival

Several bone-related parameters including those listed in

Table 3

have been demonstrated to be individual prognostic variables for overall survival in patients with bone metastases from CRPC (Table 3).
In an analysis of the prognostic value of multiple parameters in 1,901 patients with mCRPC enrolled in an international, multicenter, randomized, double-blind phase 3 trial, the following bone-specific parameters were significantly associated with longer survival (Table 3):

ALP ≤143 U/L (p<0.0001)
bone-specific alkaline phosphatase (BSAP) <146 U/L (p<0.0001)
corrected urinary N-telopeptide (uNTX) ≤50 nmol/mmol (p<0.0008)
mild or no pain (Brief Pain Inventory—Short Form [BPI-SF] score ≤4) (p<0.0001)
no previous SRE (p=0.0002)
longer time from initial diagnosis of CRPC to first bone metastasis (p<0.0001)
longer time from first bone metastasis to randomization (p<0.0001)

Table 2. Relation Between Different PSA Levels, ALP Levels, and Bone Metastases

PSA	PSA	ALP	p Value
<20	Bone Metastasis (n=6)	345.3 ± 109.9	0.01
<20	No Bone Metastasis (n=76)	169.4 ± 61.3	0.01
20-50	Bone Metastasis (n=14)	322.0 ± 146.2	0.01
20-50	No Bone Metastasis (n=46)	181.3 ± 75.1	0.01

Table 3. Bone-Specific Parameters Associated With Significantly Longer Survival

Parameter	Hazard Ratio (95% CI)	p Value
ALP ≤143 U/L	0.664 (0.559, 0.789)	p<0.0001
BSAP <146 U/L	0.683 (0.568, 0.822)	p<0.0001
Corrected uNTX ≤50 nmol/mmol	0.755 (0.640, 0.889)	p<0.0008
No previous SRE	0.748 (0.643, 0.871)	p=0.0002
Longer time from initial diagnosis of CRPC to first bone metastasis	0.997 (0.995, 0.998)	p<0.0001
Mild or no pain (BPI-SF score ≤4)	0.648 (0.563, 0.745)	p<0.0001

^{Reproduced from}^{Eur Urol.}^{Vol. 68, Issue 1. Fizazi K}^{et al.}

^{Bone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer. Pages 42-50. Copyright 2015, with permission from Elsevier.}

^{Adapted from Fizazi K}^{et al.}²⁰¹⁵

PP-PF-ONC-CA-0118-1

References
1
Smith MR et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. N Engl J Med. 2018;378(15):1408-1418.
2
Kirby M et al. Characterizing the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65(11):1180-92.
3
Saad F, So AI, Aprikian A, Finelli A, Fleshner NE, Gleave ME, et al. 2025 Canadian Urological Association-Canadian Uro-oncology Group Guideline: Metastatic castration-resistant prostate cancer (Update). Can Urol Assoc J. 2025;19(8):E276-E89.
4
Crawford ED, Stone NN, Yu EY, et al. Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence (RADAR) Group. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology. 2014;83(3):664-669.
5
O’Sullivan GJ, Carty FL, Cronin CG. Imaging of bone metastasis: an update. World J Radiol. 2015;7(8):202-211.
6
Chow KM, So WZ, Lee HJ, et al. Head-to-head Comparison of the Diagnostic Accuracy of Prostate-specific Membrane Antigen Positron Emission Tomography and Conventional Imaging Modalities for Initial Staging of Intermediate- to High-risk Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol. 2023;84(1):36-48.
7
Moslehi M, Cheki M, Salehi-Marzijarani M, et al. Predictors of bone metastasis in pre-treatment staging of asymptomatic treatment-naive patients with prostate cancer. Rev Esp Med Nucl Imagen Mol. 2013;32(5):286-289.
8
Fizazi K, Massard C, Smith M, et al. Bone-related parameters are the main prognostic factors for overall survival in men with bone metastases from castration-resistant prostate cancer. Eur Urol. 2015;68(1):42-50.