Multi-parameter spectral computed tomography for the prognosis evaluation of prostate cancer bone metastasis: a retrospective study

Introduction

Prostate cancer (PCa) is a prevalent malignant epithelial tumor affecting the male genitourinary system and ranks as the second leading cause of cancer-specific mortality among men globally as of 2023 (1,2). Despite improvements in detection rates, a significant number of cases are diagnosed at advanced stages, with approximately 5–15% involving bone metastasis (3-6). Commonly affected sites include the vertebrae in these advanced-stage cases (7,8). Bone metastasis in PCa can lead to severe complications, including bone pain, ineffective hematopoiesis, hypercalcemia, pathologic fractures, and skeletal-related events (8), all of which adversely affect quality of life and survival outcomes.

Evaluating treatment efficacy is essential for follow-up care, risk assessment, and treatment planning. Prostate-specific antigen (PSA), secreted by prostate epithelial cells, plays a critical role in the early screening, diagnosis, tumor staging, biochemical recurrence monitoring, and prognostication of PCa (9,10). Monitoring serum PSA levels is vital for post-treatment follow-up in patients with bone metastasis; however, reliance solely on PSA may lead to delayed or excessive diagnoses. Therefore, comprehensive imaging examinations are imperative (11,12). Whole-body bone scintigraphy (WBS) serves as the primary tool for detecting osteogenic metastatic lesions; however, its non-specific tracer uptake can result in false positives and lacks high resolution and anatomical detail (13,14). Computed tomography (CT) scans enhance the detection of bone lesions and provide precise evaluations. Positron emission tomography (PET) combined with CT is crucial for diagnosing changes in lesion activity or structure, despite its high cost and radiation exposure (15-18). Among these imaging modalities, prostate-specific membrane antigen (PSMA) PET/CT is recommended by international guidelines for the staging of high-risk PCa and the evaluation of disease recurrence (19,20). However, it is important to note that PSMA PET/CT may yield false-negative results in cases of ductal variant PCa (21). Furthermore, in regions where PSMA PET/CT is not universally accessible, conventional imaging techniques such as WBS continue to play an important role in routine clinical practice. Magnetic resonance imaging (MRI) offers superior clarity when displaying bone marrow involvement and enables timely detection of metastatic lesions (22,23); nevertheless, the high costs and lengthy scanning times associated with MRI pose challenges to its routine use for whole-body assessments.

Dual-energy CT (DECT) represents an emerging imaging technique that utilizes low- and high-energy X-rays to differentiate materials while generating multiple image types, including virtual monoenergetic images (VMIs) ranging from 40 to 140 keV (kiloelectron volt), spectrum curves effective atomic numbers alongside material basis pairs (24,25). DECT facilitates material identification while supporting qualitative and quantitative analyses through multi-parameter imaging techniques. Bone density, closely correlated with mineral content such as hydroxyapatite (HAP), can be analyzed more effectively using DECT. Huang et al. (26) demonstrated that VMIs at 70 keV and material basis pairs (HAP-water, water-HAP, cortical bone-water, water-cortical bone) enhance the detection of bone metastatic lesions, including subtle isodense lesions. Another study indicated that water-HAP images markedly improved diagnostic accuracy for detecting bone metastasis compared to conventional CT (27). The HAP-water and water-HAP imaging modalities are beneficial for patients with contraindications to iodine contrast. Despite DECT’s enhancements in identifying bone metastasis, its efficacy in the context of prostate cancer bone metastasis (PCa-BM) remains inadequately established. Our study aims to evaluate the value of DECT in monitoring treatment responses for PCa-BM and to compare its diagnostic effectiveness with WBS during post-treatment follow-up. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-318/rc).

Methods

This retrospective study, conducted at a single center, was non-interventional and approved by the Ethics Committee of Nanjing Drum Tower Hospital (Nanjing, China; No. 2022-103-01). The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Informed consent was waived due to the retrospective nature of this study.

Patients

A total of 120 patients diagnosed with PCa-BM were recruited from November 2020 to October 2023. All patients were pathologically confirmed to have PCa and diagnosed with bone metastasis using imaging methods. During the follow-up process, 46 patients who met the criteria were ultimately included in the study. The inclusion criteria were as follows: (I) clinically confirmed cases of bone metastasis originating from PCa; (II) diagnosis made using multiple imaging modalities, such as CT, MRI, and WBS, utilizing at least two distinct diagnostic methods; (III) availability of data from a minimum of two DECT examinations with a follow-up interval exceeding four months; and (IV) bone metastasis lesions located in the vertebrae, which typically exhibit circular or oval shapes with diameters ranging from 0.5 cm to not more than two-thirds the size of the vertebra, ensuring that all included lesions are representative when measured. Patients not meeting the criteria outlined in items (I), (III), and (IV), especially those presenting diffuse systemic metastases, were excluded from further consideration (Figure 1). All participants had their serum PSA levels monitored concurrently through laboratory blood sampling during routine imaging sessions. During each follow-up visit, patients underwent DECT imaging first, followed by WBS the following day.

Figure 1 Study flowchart. DECT, dual-energy computed tomography.

DECT protocol

DECT images were acquired using a 128-row multidetector CT scanner (Revolution ES, GE Healthcare, Waukesha, WI, USA). This scanner features a single X-ray tube and one detector, allowing for rapid alternation between two distinct tube voltages: 80 and 140 kVp. The CT scan parameters were as follows: scan type—helical and beam; rotation time—0.8 seconds; configuration—40 mm; helical pitch—0.9875:1; current—385 mA; total scan time—3.0 to 4.0 seconds; layer thickness—5 mm; reconstruction thickness—1.25 mm. The mean volumetric CT dose index recorded was 12.439 mGy/cm.

WBS protocol

The patient received an intravenous injection of technetium-99-methylene diphosphonate (⁹⁹TCm-MDP) at a dose of 20 to 30 mCi before the examination and consumed 800 to 1,000 mL of water. WBS was performed 3 to 4 hours post-injection with Philips Bright View system, which is equipped with a low-energy, high-resolution collimator with a peak of 140 keV, a matrix size of 256×1,024, a window width of 20%, and a bed speed ranging from 12 to 14 cm/min. The WBS was performed using two-dimensional whole-body skeletal planar imaging, with additional localized magnified images acquired as necessary; SPECT/CT imaging was not included.

Image analysis

DECT image analysis

Following the completion of patient examinations, the acquired images were transferred to a standard DECT workstation (GSI Viewer, AW 4.7, GE Healthcare, Waukesha, WI, USA) for image processing and data measurement, utilizing specialized GSI Volume Viewer software. Two radiologists with 3 years of experience in genitourinary radiology collaborated to measure and independently assess all image data objectively. In cases of disagreement between the two readers, a third radiologist with 15 years of experience in genitourinary radiology conducted a subsequent analysis, and their findings were deemed conclusive. Clinical and histological information was blinded to all three radiologists. The CT values (in Hounsfield Units, HU) for each single energy level, as well as the differing density values (ρ) of material base pairs (mg/cm³), were measured for both normal vertebrae and metastatic lesions during the venous phase using. The measurements were executed using the default 70 keV imaging setting on the machine’s transverse sections. The data concerning the region of interest (ROI), including CT values for each energy level (ranging from 40 to 140 keV) and density measurements for various material basis pairs (HAP-water, water-HAP), were saved as an Excel file format on the workstation. The ROI of normal vertebrae was selected from vertebrae exhibiting no pathological changes, such as compression fractures, with an area of approximately 0.5–1.0 cm². ROIs were established from the middle vertebra as well as adjacent upper and lower levels, and the average value was subsequently calculated. Each patient’s vertebrae were systematically measured, yielding a range of CT values for each single energy level and density values for different material basis pairs. The ROI for the bone metastatic lesion encompassed over two-thirds of the lesion’s entirety. Measurements were recorded across three levels: the largest level in the transverse section, as well as at neighboring upper and lower levels. The average of these measurements was adopted as the representative CT value and density value for both normal vertebrae and the respective lesion (Figure 2).

Figure 2 DECT assessment of CT value and density in normal vertebrae and bone metastasis. Axial (A) and sagittal (B) views indicated that the ROI for normal vertebrae is centrally located within the vertebral body. Sagittal (C) and axial (D) views demonstrated HAP-water images of a PCa-BM, with the ROI centrally positioned within the lesion, encompassing more than 2/3 of its area. Axial (E) view illustrated water-HAP images of a PCa bone metastatic lesion. The green circles indicate the ROI. CT, computed tomography; DECT, dual-energy computed tomography; HAP, hydroxyapatite; PCa, prostate cancer; PCa-BM, prostate cancer bone metastasis; ROI, region of interest.

At a given energy level, the CT values and density measurements of the lesions were reconstructed as follows:

CTvalue(or)ρ(materialbasispairs)=CT2(or)ρ2−CT1(or)ρ1[1]

Here, CT₁ denotes the initial follow-up measurement taken after patient enrollment, and ρ₁ represents the corresponding material basis pair value obtained at that time. In parallel, CT₂ and ρ₂ refer to the second follow-up measurement post-treatment. The majority of bone metastatic lesions in PCa are classified as osteogenic, with a minority exhibiting a mixed osteogenic and osteolytic phenotype, while purely osteolytic metastases are extremely rare. We defined progressive disease as changes in CT values and ρ (HAP-water) that exceed the upper limit of the normal fluctuation range. In contrast, changes that fall within or below the lower limit of the normal fluctuation range are considered effective. Conversely, ρ (water-HAP) exhibits an opposite trend.

WBS image analysis

The WBS images were independently interpreted by a nuclear medicine physician with 15 years of experience in nuclear imaging, who was not involved in the evaluation of the DECT images and processes extensive expertise in interpreting WBS images. To mitigate the treatment-induced “flare effect” associated with WBS, a minimum interval of three months between examinations was established (28). WBS evaluates bone metastasis based on the following criteria: (I) complete response: total disappearance of initial lesions on WBS images; (II) partial response: a reduction in lesions, accompanied by decreased uptake of osteogenic lesions; (III) stable disease: absence of significant changes observed in lesions, with bone lesions exhibiting slow alterations classified as stable or unchanged after a minimum of 8 weeks of treatment; and (IV) progressive disease: enlargement of original lesions, increased uptake, or the emergence of new lesions (29). Complete response, partial response, and stable disease were classified as effective outcomes, while progressive disease was deemed ineffective.

Response evaluation criteria

Our study cohort included both castration-resistant and hormone-sensitive PCa patients. In this study, researchers utilized the criteria outlined by the Prostate Cancer Clinical Trials Working Group 3 (PCWG3) and European Association of Urology guidelines to assess PCa regression (30). The following criteria were employed to determine PCa treatment outcomes: Progressive disease: (I) failure to control PSA levels, indicated by a rise above baseline that persists across two follow-up visits separated by more than three months; (II) radiological progression of bone disease, characterized by the emergence of two or more new lesions detected on WBS at 9 weeks post-initial treatment, which necessitated validation through an additional scan at 6 weeks demonstrating the persistence of the new lesions; (III) radiological progression in soft tissues did not require corroboration through further imaging. If any combination of criteria (II) or/and (III), with or without (I), was met, it indicated progressive disease; otherwise, the treatment was considered effective.

Statistical analysis

All data were imported into a computer system for statistical analysis utilizing SPSS version 26.0. The Pearson Chi-squared test was used to analyze whether there were statistically significant differences between the two groups regarding the rates of DECT and WBS. Following the PCWG3 guidelines for clinical outcomes in PCa, we evaluated the capability of DECT multi-parametric imaging to monitor bone metastatic lesions associated with PCa. This assessment utilized the Pearson Chi-squared test to measure accuracy, specificity, sensitivity, positive predictive value (PPV), and negative predictive value (NPV). Furthermore, the effectiveness of PCa treatment was evaluated through receiver operating characteristic (ROC) curve analysis, which involved calculating the area under the curve (AUC). A P value of less than 0.05 was considered statistically significant.

Results

Patient characteristics

During the study period, 46 out of 120 consecutive patients diagnosed with PCa-BM met all inclusion criteria for this investigation (Figure 1). Among these, 29 patients (mean age 70.7±7.5 years; a total of 132 lesions) were clinically diagnosed as treatment-effective (stable or improved). Additionally, 17 patients (mean age 66.6±9.3 years; a total of 74 lesions) were diagnosed with progressive disease. Throughout the follow-up period, serum PSA levels were measured periodically for each patient. Twenty-two patients exhibited elevated levels, while 24 patients demonstrated either stability or no elevation (Table 1).

Qualitative image assessment

Our research included a total of 206 metastatic vertebrae. The normal fluctuation range of CT values for healthy vertebrae at various keV levels—including 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, and 140 keV—was observed as follows: −7.28±19.75, −4.52±16.20, −3.24±12.82, −2.35±11.38, −1.84±10.52, −1.45±10.01, −1.26±9.66, −1.45±9.43, −1.69±9.28, −1.84±9.16, and −1.96±9.07 HU. Additionally, the fluctuation range of material basis pairs in healthy vertebrae varied as follows: HAP-water, 0.43±3.79 mg/cm³; and water-HAP, 2.20±8.02 mg/cm³. These values provided essential benchmarks for assessing changes in vertebral metastasis following treatment. The Pearson Chi-squared test results indicated statistically significant changes between DECT-based venous phase HAP-water values and WBS uptake (P=0.019). The results of CT values and water-HAP density changes across the range of 40–140 keV (at 10 keV intervals), compared with WBS, are shown in Table 2, with no significant differences observed (P>0.05).

Comparison of diagnostic performance between DECT multi-parameter images and clinical diagnosis

We focused on metastatic vertebrae as the study subjects, utilizing clinical diagnosis as a reference criterion. The sensitivity, specificity, PPV, NPV, and AUC across energy levels from 40 to 140 keV, along with the water-HAP parameter, are presented in Table 3 and Figure 3A. At 40 keV, sensitivity was recorded at 47.73%, while specificity was noted at 39.19%. The PPV stood at 58.33% and NPV at 29.59%, resulting in an AUC of 0.565. Sensitivity exhibited slight improvements at both the 50 and 60 keV levels, reaching values of exactly 50.00%. However, specificity decreased to approximately 36.49%, with PPV and NPV remaining consistent with the 40 keV data, resulting in an AUC of approximately 0.568. At 70 keV, sensitivity increased to 53.03%, but specificity declined to 35.14% with corresponding PPV around 59.32% and a stable NPV of approximately 29.55%, yielding an AUC of approximately 0.4. Increasing energy levels beyond this point, we observed gradual variations in sensitivity and specificity, with values of 54.55% and 32.43%, respectively, at 80 keV, resulting in an AUC of 0.435. At 90 keV, sensitivity improved to 57.58%, while specificity remained at 32.43%. The corresponding PPV was around 60.32%, while NPV was 30.00%, yielding an AUC of 0.450. The highest sensitivities were documented at 100 and 110 keV, both achieving 58.33%, with consistent specificities of 35.14%, resulting in an AUC of 0.467. At 120 and 130 keV, sensitivity was 56.06%, while specificities remained at 36.49%, leading to AUC values of 0.463. Finally, at 140 keV, sensitivity remained at 56.06%, whereas specificity increased to 37.84%, yielding an AUC of 0.469. In contrast, the water-HAP parameter exhibited a sensitivity of 60.61%, specificity of 24.32%, PPV of 58.82%, NPV of 25.71%, and an AUC of 0.425.

Figure 3 ROC curves of DECT multi-parametric images alone (A) and combined with serum PSA (B) for evaluating the efficacy of PCa bone metastatic lesions. DECT, dual-energy computed tomography; HAP, hydroxyapatite; PCa, prostate cancer; PSA, prostate-specific antigen; ROC, receiver operating characteristic.

Comparison of diagnostic performance between DECT multi-parameter images and clinical diagnosis combined with serum PSA levels

A comparative analysis of diagnostic performance between DECT multi-parameter images in conjunction with clinical diagnosis and serum PSA levels is detailed in Table 4 and Figure 3B. At 40 keV, the combination with serum PSA yielded sensitivity of 91.67%, specificity of 35.14%, PPV of 71.60%, NPV of 70.27%, and an AUC of 0.634. At both the 50 and 60 keV settings, sensitivity improved to 93.18%, while specificity decreased to 32.43%. The PPV was noted to be slightly lower at 71.10%, while the NPV increased to 72.73%, resulting in an AUC of 0.628. The 70 keV setting showed a slight improvement in sensitivity to 93.94% and an NPV increase to 74.19%, but specificity dropped further to 31.08% and PPV to 70.86%, producing an AUC of 0.625. At the 80 keV measurement, sensitivity remained stable at 93.94%, while specificity fell to 28.38%. The PPV was reported at approximately 70%, and NPV remained consistent, yielding an AUC score consistently lower than earlier measurements. Data collected from higher energy settings, such as 90 keV, showed no change in sensitivity but maintained low specificity (28.38%) along with similar PPV (70%) across multiple trials. For measurements ranging from 100 keV to 140 keV, sensitivity remained around 93–94%, while specificities fluctuated minimally between 31–34%. The water-HAP parameter, when combined with serum PSA, demonstrated a notable decrease in performance metrics, achieving a sensitivity of 92.42%, a significantly lower specificity of 24.32%, alongside corresponding values for PPV (68.54%) and NPV (64.29%).

Discussion

PCa predominantly affects middle-aged and older men (1,2). Localized PCa is typically asymptomatic, and by the time symptoms do appear, the disease has often advanced to a metastatic stage. The spine’s complex venous system, which lacks valves and features slow blood flow (2,7), creates favorable conditions for bone metastasis in PCa. Among PCa patients with bone metastasis, approximately 60% to 70% initially develop metastasis in the axial skeleton, particularly in the vertebrae (7,8,31,32). Various imaging modalities, combined with laboratory indicators, can enhance PCa classification and facilitate the development of individualized treatment plans. Nonetheless, there is a scarcity of studies assessing the impact of treatment on bone metastasis in PCa.

WBS is currently regarded as the standard approach for diagnosing and monitoring the therapeutic efficacy of bone metastasis from PCa according to the PCWG3 guidelines (30). WBS detects lesions associated with bone metastasis through changes in skeletal blood flow and metabolism using radioactive substances. While WBS exhibits high sensitivity, it has relatively low specificity. DECT generates VMIs across energy levels from 40 to 140 keV (25). Previous research has shown that image quality varies among different tissues at varying energies; specifically, low-energy VMI enhances the contrast between blood vessels and surrounding tissues, while high-energy VMI mitigates artifacts such as calcification or metal interference (33,34). The scanning mode employed by DECT facilitates the generation of precise material decomposition images (25). Bone comprises approximately 30% organic matter (primarily proteins) and 70% inorganic matter (mainly HAP) (35,36). Water-HAP material decomposition images can effectively isolate HAP components from bone tissue using material separation techniques.

In this study, we investigated changes in the CT values of metastatic lesions related to PCa across energy levels from 40 to 140 keV (in 10 keV intervals), analyzing the densities of material pairs (HAP-water; water-HAP) during the venous phase involving a total of 206 lesions. Our results indicated that the 40–140 keV and water-HAP images obtained from DECT did not show statistically significant differences compared to WBS in evaluating the regression of PCa-BM. This suggests that VMIs at various energy levels, along with water-HAP images, possess comparable effectiveness to WBS in assessing outcomes related to PCa-BM. Consistent with the findings by Huang et al. (26) and Ishiwata et al. (27), our study further corroborates the utility of water-HAP material decomposition DECT in detecting bone metastases. Moreover, our analysis revealed a statistically significant difference between HAP-water images, indicating their inferiority relative to WBS for evaluating PCa-BM outcomes. Additionally, we demonstrated a correlation between changes in HAP content within PCa metastatic lesions and tracer uptake levels observed via WBS.

We also compared diagnostic indices when utilizing DECT multi-parametric imaging alone versus in combination with serum PSA. Our findings showed that employing DECT images across varying keV levels alongside water-HAP images resulted in an incremental increase in sensitivity—from 47.73% to 56.06%—as energy levels rose; notably, water-HAP images exhibited the highest sensitivity among all modalities assessed. The integration of serum PSA with DECT significantly enhanced sensitivity, exceeding 90%. However, DECT alone had relatively low specificity, exhibiting minimal variation as energy levels increased, ranging from 32.43% to 39.19%. Among all imaging techniques evaluated, water-HAP images demonstrated the lowest specificity. The PPV ranged from 58.33% to 61.67%, while the NPV varied between 25.71% and 32.56% when using DECT as a standalone diagnostic tool. We subsequently calculated the AUC for multi-parametric images using only DECT, which yielded values between 0.425 and 0.568. In contrast, AUC values considerably increased when DECT was combined with serum PSA measurements, ranging from 0.584 to 0.635. In summary, while multi-parametric images obtained via DECT alone exhibited moderate sensitivity and low specificity, their combination with serum PSA markedly enhanced sensitivity and NPV, facilitating a more accurate assessment of bone lesions. DECT has advantages such as shorter imaging time, lower cost, and reduced radiation exposure compared to WBS imaging techniques. Therefore, utilizing VMIs at different energy levels and water-HAP images from DECT combined with serum PSA is a viable strategy for evaluating the efficacy of PCa-BM in future assessments.

However, there are several limitations in this study. Firstly, our sample included both castration-resistant and hormone-sensitive PCa patients. However, due to the relatively small sample size of this study, stratified analyses based on treatment modalities and evolving findings would lack sufficient statistical power and may lead to potentially misleading interpretations. Secondly, time gaps of at least 3 months between DECT scans, WBS scans, and PSA measurements, due to variations in individual treatment plans, could impact our findings. Additionally, all ROIs were manually outlined, which could lead to potential errors during selection before and after treatment. Lastly, the range defining normal HAP fluctuation in bone lesions was determined solely by our researchers without established guideline standards.

Considering these considerations, it is necessary to expand our sample size through multi-center collaborations in future studies while grouping PCa patients based on their specific treatment approaches to reduce potential bias in the results.

Conclusions

Future studies with larger cohorts and optimized DECT protocols may further improve the diagnostic performance of DECT for PCa-BM. Given the rapid advancements in molecular imaging, PSMA PET has emerged as the gold standard for the detection and monitoring of PCa-BM. Conducting a direct comparison between DECT and PSMA PET would constitute a valuable direction for future research. DECT may serve as a complementary or alternative imaging modality in settings where PSMA PET/CT is unavailable or contraindicated. In such cases, the risk of potential false-negative findings with DECT should be carefully considered. We aim to conduct a comprehensive quantitative analysis of compositional changes in PCa-BM using DECT multi-parametric images to assess disease progression. Additionally, we aspire to enhance the clinical evaluation of the efficacy of PCa treatments for bone metastasis.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-318/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-318/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-318/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the institutional review committee (Ethics Committee of Nanjing Drum Tower Hospital, Nanjing, China; No. 2022-103-01). The informed consent was waived due to the retrospective nature.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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