Review of imaging techniques for evaluating morphological and functional responses to the treatment of bone metastases in prostate and breast cancer.

Introduction

Bone metastases are very common complications in certain types of cancer; their physiopathology is shown in Fig. 1 . In necropsy studies, bone metastases have been reported in up to 70% of patients with prostate or breast cancer; in the latter case, bone is the first metastatic site in approximately 50% of patients [ 1 ]. The first metastatic site for bone metastases is the axial skeleton in 60–70% of patients with prostate cancer [ 2 , 3 ] and in 40–50% of patients with breast cancer [ 3 , 4 ]. Bone dissemination is also important because it causes significant comorbidities. Accordingly, the most frequent skeletal-related events (SREs) are spinal cord/nerve root compression (3.1% of patients with prostate cancer and bone metastasis; 2% of patients with breast cancer and bone metastases), pathological fractures (18% of patients with prostate cancer and bone metastasis and 12% of patients with breast cancer and bone metastases), and bone marrow infiltration (2% in patients with prostate cancer and 4% in those with breast cancer) [ 5 , 6 ]. These complications negatively impact the patients’ quality of life and functional status; thus, early detection is necessary for the implementation of immediate therapeutic measures to reduce the risk of skeletal complications and improve survival and quality of life [ 7 ]. Fig. 1 Drawing representing the physiopathology of bone metastases. The bone marrow (BM) is an attractive niche for certain tumor cells, owing to a number of physical, biochemical, and cellular properties. The relationship between the bone marrow niche and infiltrating tumor cells is dynamic. Tumor cells colonize, alter and hijack the niche, making the microenvironment even more hospitable for them and interacting with osteoblasts and osteoclasts causing osteoblastic and osteolytic lesions, which really represent a continuum, and facilitating tumor growth (the so-called “Vicious Cycle”). BMP bone morphogenic proteins, CLP common lymphoid precursor, CMP common myeloid precursor, DKK-1 Dickkopf1, GDF15 growth differentiation factor 15, LC lymphoid cell, MSC mesenchymal stromal cell, MHSC multipotential haematopoietic stem cell, osteomac osteal macrophage, OPG osteoprotegerin, PTH parathormone, RANKL receptor activator for nuclear factor κB ligand. Courtesy of Roberto García Figueiras, Radiology department, Complexo Hospitalario Santiago de Compostela (Spain)

Early detection of bone metastases is also essential for accurate tumor staging and optimal oncological treatment. In breast cancer, there is little evidence that early detection of bone metastases in asymptomatic or minimally symptomatic patients has a significant impact on quality of life and survival [ 8 ]. However, as current therapies for advanced metastatic cancer improve, the early treatment of small-volume metastases may become a more effective strategy. In fact, in metastatic prostate cancer, it has been shown that active treatment of asymptomatic or minimally symptomatic disease leads to benefits in disease-free survival and overall survival [ 9 , 10 ]; thus, some clinical guidelines and consensus statements now recommend the prospective detection of metastatic disease in patients with asymptomatic prostate cancer, aiming at earlier active treatment either with chemotherapy or androgen deprivation therapy [ 11 , 12 ]. Furthermore, the therapeutic strategy for bone metastases of prostate cancer changes according to the number of metastases and their location [ 13 ]. In oligometastatic breast cancer, a prospective phase II multicenter trial found that radical radiotherapy to all metastatic sites may improve progression-free survival [ 14 ]. Similar improvement in PFS was found in a randomized phase II trial where 99 patients with several tumor types, including breast ( n = 18) and prostate ( n = 16) cancer, and 1–5 metastatic lesions were randomized to receive palliative standard-of-care (SOC) or SOC plus stereotactic radiotherapy; in this trial an improvement in the 5-year OS rate from 17% among those who received SOC to 42% among those assigned to SOC plus stereotactic radiotherapy [ 15 ].

At staging, the objectives of imaging techniques are to identify the exact number of metastatic foci and their location, to quantify the tumor load and to exclude complications, such as pathological fractures or spinal cord compression. In addition, imaging can guide biopsies if considered necessary and has a growing role in therapy monitoring [ 16 ].

There are two pure radiographic manifestations of bone metastases: osteoblastic lesions, when bone-forming processes prevail and osteolytic lesions when resorptive processes are dominant; however, it is common to find mixed features in radiological assessment. Osteolytic metastases cause more clinical complications [ 5 ].

There is no consensus or universal standard approach for detecting bone metastases in cancer patients with imaging. The choice of the most appropriate imaging strategy should be selected according to the clinical presentation and the underlying histological tumor type because osteoblastic and osteolytic patterns differ. In general, metastatic bone X-ray series are not considered a useful tool in the assessment of bone metastases [ 17 ]. Bone scintigraphy is commonly performed in the initial staging of patients with known cancer capable of producing mixed metastases (lytic and blastic) or purely blastic metastases, such as prostate cancer. However, the sensitivity and accuracy of bone scintigraphy in bone metastasis detection is significantly inferior to those of more recent modalities, such as whole-body magnetic resonance imaging (WB-MRI) with diffusion-weighted imaging (DWI) [ 18 ] or fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) [ 19 , 20 ]. These recent technologies are also known as next-generation imaging (NGI), which has shown benefits in the staging and management of prostate and breast cancers. In the particular case of prostate cancer, WB-MRI and PET/CT with new tracers (Ga-prostate-specific membrane antigen [PSMA], 18F-fluciclovine, etc.) improve the assessment of both the extent of metastatic dissemination and the response to systemic treatments [ 21 ]. In breast cancer, there has also been an important improvement in staging with the advances in imaging techniques. A prospective comparison of CT and 18-F-FDG-PET/MRI in 80 patients with breast cancer showed that the latter was able to detect all 7 patients with distant metastases without any false-positive findings while CT missed metastases in 3 patients and provided false-positive findings in 3 patients [ 22 ]. However, no unique imaging strategy is consistently superior for the evaluation of metastatic bone disease in all tumor types and clinical scenarios.

The objectives of the treatment of patients with bone metastases include maximizing pain control, preserving and restoring function, minimizing the risk of SREs, stabilizing the skeleton if necessary and improving local tumor control. The current therapeutic options include pain management with analgesics, which can be administered in combination with (1) osteoclast inhibitors or bone modifying agents (including bisphosphonates and denosumab); (2) systemic cancer therapy (chemotherapy, immunotherapy, targeted therapies and hormone therapy); (3) radiotherapeutic treatment (external beam radiation therapy (EBRT), stereotactic body radiation therapy (SBRT)); (4) bone-targeting radiopharmaceuticals (e.g., samarium-153, strontium-89, and radium-223); (5) surgery, which is typically reserved for patients with a complete or imminent pathological fracture; and (6) local treatments, such as vertebroplasty, kyphoplasty, and image-guided thermal ablation [ 23 , 24 ].

Treatment recommendations should be individualized according to the symptoms and impact on the quality of life of the patient, his or her functional status, the clinical status of the disease (extensive metastatic or oligometastatic disease), the estimated life expectancy, and whether there is an imminent or actual fracture in the affected bone [ 25 ].

To effectively manage patients with metastatic bone disease, it is essential to have consistent, reproducible, and validated methods to evaluate the response to treatment. The imaging criteria most commonly used are the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. These and other similar classifications are predominantly focused on the physical measurement of solid tumors. A disease that cannot be easily measured with a ruler or calipers, as with most bone metastases, is designated nonmeasurable, and these patients are often not eligible for clinical trials, which may be the only available source of therapy. Nevertheless, current methods of evaluating therapeutic responses in cancer with bone metastasis remain problematic with wide variations in clinical practice. Among the currently available imaging modalities, WB-MRI and hybrid techniques combining morphological and functional data are the most sensitive and specific, and PET/CT and PET/MRI are becoming increasingly important in this regard [ 26 , 27 ].

A group of experts selected and supported by the Spanish Society of Medical Oncology (SEOM), the Spanish Society of Medical Radiology (SERAM), and Spanish Society of Nuclear Medicine and Molecular Imaging (SEMNIM) met to discuss and provide an up-to-date review of our current understanding of the biological mechanisms through which tumors spread to bone and describe the imaging methods available to diagnose bone metastasis and monitor their response to oncological treatment, focusing on patients with breast and prostate cancer. To this end, the experts met in Madrid (Spain) to agree on the topics to be addressed in the consensus and distribute these topics among the experts. Afterward, all experts revised several drafts prepared until an agreement on the final version was reached.

Biological mechanisms of bone metastasis or pathophysiology and molecular biology of bone metastasis

Several biological factors that predispose patients to bone dissemination in breast and prostate cancer have been described in recent years. When tumor cells escape the primary tumor, the majority do not survive in the bloodstream with only 0.02–0.1% of those that reach the blood being viable [ 1 ]. Tumor cells with positive expression of the chemokine receptor CXCR4 are mainly attracted to the bone stroma through the chemokine CXCL12. The high expression of adhesion molecules, such as integrins and VCAM-1, allows the binding of circulating tumor cells (CTCs) to the bone marrow (BM) stroma [ 7 ]. Once they reach this hematopoietic cell niche in the BM, tumor cells can undergo different dormancy periods. The BM microenvironment is characterized by low pH and oxygenation and elevated levels of extracellular calcium, which promote this dormancy and resistance phenomenon. At a certain time, dormant tumor cells transform into tumor-initiating cells (TICs) that begin the bone colonization process and produce an imbalance in the homeostatic mechanisms that regulate bone formation and resorption (bone turnover), ultimately leading to the establishment of metastasis [ 7 , 28 ]. These regulatory mechanisms include the RANK/RANKL pathway, which coordinates the relationship between osteoblasts and osteoclasts. When these molecules bind to tumor necrosis proteins (tumor necrosis factor—TNF) through the expression of the osteoprotegerin (OPG) receptor, they stimulate bone resorption through osteoclasts, leading to lytic lesions. Overexpression of inhibitory factors of the Wnt pathway (such as DKK-1, among others) also promotes the formation of lytic lesions. In the case of blastic lesions, the Wnt/ET/BMP pathway is the main regulatory mechanism described. This pathway plays a crucial role in osteoblasts’ differentiation, function, and development [ 29 , 30 ].

Diagnostic tests for the initial diagnosis and staging of bone metastasis

Imaging modalities play a leading role in the early and accurate detection of bone involvement in the initial staging process, identifying complications, such as fractures or spinal cord compression, and evaluating response to local and systemic therapies.

The detection of metastatic bone disease rests on two possible foundations according to the imaging modality: the direct identification of the tumor and its tissue infiltration or the visualization of the bone reaction in the presence of tumor cells [ 31 ]. Notably, the biological basis of osteoblastic and osteolytic lesions is completely different. Bone resorption and bone formation are two intimately linked processes in health, but bone turnover is elevated and distorted in malignant lesions [ 32 ]. In this manner, osteoblastic metastases show a reduction in bone resorption and an increase in the stimulation of osteoblasts. On the other hand, osteolytic lesions show reduced osteoblastic activity and increased osteoclast stimulation.

Based on these foundations, anatomical and functional diagnostic tests have been developed that offer decisive and complementary information to classify patients as having advanced-stage cancer.

Bone X-ray

The use of two orthogonal radiographic projections of an area that is painful or suspicious for an acute event in an oncological patient is, in many cases, the initial method for bone metastasis detection. Although it uses ionizing radiation, it is an inexpensive, fast and accessible exploration—that allows detection of the presence of lytic lesions (with greater than 50% destruction of the mineralized bone), blastic lesions, mixed lesions or complications, such as pathological fractures [ 33 ]. However, the use of the classical metastatic bone series to systematically exclude the presence of metastasis has not been recommended for years given its low diagnostic yield; thus, its role has been relegated to the study of doubtful or clinically significant areas.

Computed tomography

Computed tomography (CT) is a primarily structural technique that provides a high spatial resolution and an adequate evaluation of the trabecular and cortical bone components. To detect lytic lesions, bone destruction of at least 20–30% is required. Therefore, the role of this technique in the detection of early metastatic bone disease is limited, especially in cases in which bone destruction has occurred in osteoporotic bone or bone with degenerative changes [ 34 ]. In addition, CT shows modest results in the detection of malignant infiltration of the bone marrow, making it difficult to differentiate between small metastases and normal fat bone marrow. For example, in a recent meta-analysis of the detection of bone metastases with various imaging techniques, the average sensitivity and specificity of CT were 73 and 95%, respectively. The sensitivity was significantly lower than those of bone scintigraphy, magnetic resonance imaging (MRI), and positron emission tomography (PET), although its specificity was greater than that of bone scintigraphy and similar to those of PET and MRI [ 35 ]. With the advent of dual and spectral CT, which has the unique ability to differentiate materials by their atomic number, new perspectives have been opened in assessing metastatic bone disease as they allow a better assessment of bone composition. Preliminary results have shown similar capabilities of dual energy CT to bone scintigraphy in the detection of bone metastases [ 36 ]. Finally, a recent report has shown that spectral CT and WB-MRI equally perform in detecting breast cancer metastases on a per-patient basis, and are superior to conventional CT. Specifically in detecting of metastatic bone lesions on a per-lesion basis, there were non-significant differences in sensitivity and specificity between spectral CT and WB-MRI, although, WB-MRI showed a significant superior area under the curve (AUC) [ 37 ].

Diffusion-weighted whole-body magnetic resonance imaging

MRI is a technique that classically provides structural information with excellent average sensitivity and specificity in detecting of bone metastases equivalent at least to those of 18-FDG-PET/CT due to its excellent tissue contrast [ 35 ]. MRI allows the adequate detection and characterization of any bone metastasis, including lytic, blastic or mixed metastases, and has the advantage of not using ionizing radiation. MRI is also the technique of choice to detect complications of metastasis, such as pathological fractures or spinal cord compression in the case of vertebral lesions, allowing an accurate evaluation of the extension to adjacent structures and the possible infiltration of soft tissues or neurovascular bundles. In addition, it is an excellent technique for the early detection of bone marrow infiltration, which precedes the morphological changes produced by bone metastases and, therefore, for the early detection of metastatic bone disease [ 38 ].

Using state-of-the-art equipment, recent technological advances have allowed performing whole-body studies that cover the axial skeleton or even the extremities in examination times of less than 30 min. Traditional morphological sequences can be complemented with functional information provided by techniques, such as perfusion, proton spectroscopy or diffusion, that quantitatively assess tumor angiogenesis and permeability, metabolism and cellularity, respectively [ 39 ]. Diffusion, which assesses the Brownian motion of free water, allows the quantitative determination of the degree of tissue interstitial occupation and indirect estimation of the cellularity of a tissue based on the apparent diffusion coefficient (ADC). The diffusion-weighting is controlled by the b value, a factor that reflects the strength and timing of the gradients during the imaging acquisition. In addition, DWI is the only functional or molecular MRI technique that can be applied to whole-body (WB)-MRI studies.

State-of-the-art WB-MRI protocols (Table 1 ) should include T1- and T2-weighted morphological sequences without and with fat suppression in addition to diffusion-weighted sequences and should always be interpreted jointly. In addition, if T1- or T2-weighted Dixon sequences are used, they allow differentiation and quantification of the fat and water components of the bone marrow, allowing a better understanding of the changes produced in the bone marrow with different therapies [ 32 ]. The multiparametric information derived from WB-MRI has shown global results similar to those for 18-Fluorodeoxyglucose ( 18 FDG)-PET/CT in detecting of metastasis, although WB-MRI is considered superior in evaluating of hepatic and cerebral secondary involvement. However, it has shown more limited results than PET in the evaluation of pulmonary and lymph node metastases. In the specific case of bone metastases, diffusion-weighted WB-MRI is considered the whole-body imaging technique with greatest diagnostic accuracy for their evaluation, with a greater performance than scintigraphy or PET/CT [ 40 ]. Table 1 Recommended protocol for diffusion-weighted WB-MRI for the evaluation of bone metastases Region Sequence Plane Head to thighs STIR Coronal Head to thighs Dixon TSE T1 Coronal Head to thighs TSE T2 Axial Head to thighs Dixon GE T1 Axial Head to thighs Diffusion-weighted imaging Axial or coronal Spinal column STIR Sagittal Spinal column TSE T1 Sagittal STIR short-tau inversion-recovery, GE gradient echo, TSE turbo spin echo

A meta-analysis published in 2020 confirmed that WB-MRI was superior to bone scintigraphy in the detection of bone metastasis with higher sensitivity (94 vs. 80%, respectively) and diagnostic accuracy and higher but comparable patient-based specificity (99 vs. 95%, respectively) [ 41 ]. Similarly, the SKELETA prospective clinical trial evaluated 26 patients with breast cancer and 27 with prostate cancer (PCa) with a high risk of metastatic bone disease using bone scintigraphy, single photon emission computed tomography (SPECT), SPECT/CT, 18F-sodium-fluoride ( 18 F-NaF)-PET/CT and diffusion-weighted WB-MRI. The areas under the curve (AUCs) for the detection of bone metastases by SPECT/CT, 18 F-NaF-PET/CT and diffusion-weighted WB-MRI were significantly higher than those of bone scintigraphy and SPECT. Additionally, the sensitivity and AUC in the lesion-based analysis were significantly higher for 18 F-Na F-PET/CT and diffusion-weighted WB-MRI compared with the remaining techniques. In addition, similar results were noted between the two techniques despite fewer equivocal lesions for WB-MRI [ 42 ]. In addition, another recent meta-analysis evaluating the detection of bone metastases in PCa showed superior results for WB-MRI (sensitivity 0.95, specificity 0.96, and AUC 0.98) compared to bone scintigraphy (sensitivity 0.79, specificity 0.82, and AUC 0.88) and choline-PET/CT (sensitivity 0.87, specificity 0.97, and AUC 0.95) [ 43 ]. Furthermore, a recent study compared the performance of diffusion-weighted WB-MRI to FDG-PET/CT in 39 patients with 239 bone metastases, and the sensitivity, specificity, overall accuracy, positive predictive value, and negative predictive value were 93.0%, 87.8%, 89.6%, 79.8%, and 96.0%, respectively, for WB-MRI and 92.5%, 92.0%, 92.1%, 85.7%, and 95.9%, respectively, for FDG-PET/CT. The specificity of WB DWIBS in detecting bone metastases was significantly lower than that of FDG-PET/CT ( p < 0.05), whereas the remaining results were not significantly different between the two techniques [ 44 ]. Finally, another meta-analysis that evaluated the detection of bone metastases from different malignant tumors showed a sensitivity and specificity greater than 90% for diffusion-weighted WB-MRI; however, the specificity for diffusion-weighted WB-MRI was lower than that for WB-MRI including only morphological series [ 45 ]. Therefore, diffusion-weighted WB-MRI has been proposed as the technique of choice to evaluate patients with bone metastases of an unknown primary tumor location [ 46 ]. In the case of bone metastases, the objectives of whole-body imaging tests for staging go beyond determining the existence of metastatic disease as it is also critical to detect disease sites and quantify disease volume. In some tumors, such as PCa, the metastatic tumor load has a high prognostic value and is critical for determining therapeutic options as well as confirming or excluding the presence of oligometastatic disease (≤ 5 metastases) as it allows more aggressive selective treatments, such as targeted radiotherapy, surgery or ablative procedures [ 27 ].

Today, WB-MRI is considered a first-line technique in the search for distant metastases of breast, prostate, and neuroendocrine tumors and in the extension study of multiple myeloma and in the evaluation of pediatric and pregnant patients with cancer [ 40 ]. WB-MRI is also considered a valid alternative in the distal staging of melanoma, lung cancer, thyroid cancer, renal cancer or colon cancer. Especially interesting is the use of MRI to perform single-step local and distal staging of gynecological, rectal and prostate tumors. Specifically regarding PCa, according to current clinical guidelines, it is only recommended to use imaging tests to exclude metastatic disease in patients with untreated PCa with an unfavorable intermediate-to-high risk of locally advanced disease and in cases of suspected relapse after treatment [ 12 , 47 ]. In this clinical scenario, WB-MRI has been proposed by several authors as an alternative to the current imaging algorithm for regional and distal staging, which includes the use of contrast-enhanced CT and bone scintigraphy. WB-MRI has demonstrated equivalent sensitivity and specificity in the detection of lymph node metastases to CT and superior results compared to bone scintigraphy for the detection of bone metastasis, allowing the avoidance of the use of two different tests with ionizing radiation and two different injections of intravenous contrast [ 48 ].

Bone scintigraphy

Bone scintigraphy (BS) with technetium-labeled diphosphonates ( 99m Tc-HDP) continues to be the technique of choice and the most widely used in the evaluation of osteoblastic or mixed metastatic bone disease [ 27 , 49 ]. The accessibility and low cost of BS and its capacity to detect osteogenic activity up to 2–18 months before the appearance of clinical, analytical or bone X-ray signs, have made this technique an essential tool in the study of initial staging.

99m Tc-HDP is a calcimimetic radiopharmaceutical; its uptake in bone is influenced by local blood flow, bone remodeling activity, and extraction efficiency. Once deposited in the bone, diphosphonates are absorbed by hydroxyapatite crystals on bone mineralization surfaces [ 50 ]. A change of only 5–10% in the lesion/healthy bone ratio is sufficient to induce pathological deposition of the radiopharmaceutical [ 23 ].

As a whole-body study, bone scanning allows the visualization of the entire skeleton in a single image, making it possible to detect appendicular lesions that are usually not included in conventional studies. Another advantage lies in its reasonably high global sensitivity (78%, which can reach 87% if SPECT tomographic acquisition is used) [ 26 ]. However, such SE leads to the detection of benign lesions with intense osteogenic activity, such as eosinophilic granulomas and fibrous dysplasia or enchondromas, as causes of false positives and low specificity in the oncological context [ 51 ]. In addition, posttraumatic bone changes and a mechanical or degenerative etiology also hinder the interpretation of scintigraph images.

In addition to these weaknesses, this technique also has limited spatial resolution, especially when only a planar image is used [ 52 ], and a practical inability to detect purely lytic lesions, which usually have a more aggressive tumor biology, in which repairing perilesional bone remodeling is not present, being the new bone formation tissue the substrate for the deposition of the labeled diphosphonates. Finally, diffuse metastatic bone dissemination with a “superscan pattern” can go unnoticed by inexperienced eyes, which would lead to incorrect disease staging and management.

SPECT imaging and, more recently, hybrid SPECT/CT imaging have been included in routine clinical practice to minimize the weaknesses of the planar image (global sensitivity and specificity of SPECT for the detection of bone metastases of 87 and 91%, respectively), allowing the evaluation of the bone structure in the three planes of space through simultaneous visualization of the anatomical image and functional or bone metabolism image [ 26 , 53 ].

Positron emission tomography

There are three classes of PET radiopharmaceuticals used to obtain bone images: 18 F-sodium fluoride, which is an osteotropic or calcimimetic element, is a specific bone marker with affinity for osteoblast activity and fixation mechanism similar to that of 99m Tc-HDP [ 54 ]; specific oncotropic markers, such as 68 Ga-HER-2 or 18 F-fluoroestradiol in the case of breast cancer or fluoromethylcholine or prostate-specific membrane antigen (PSMA) as membrane-specific antigens in the case of prostate cancer; and metabolic tracers or nonspecific oncotropic markers, such as [ 18 F] 2-fluoro-2- d -glucose (FDG) as a marker of tumor glycolytic activity [ 55 ].

The utility and applicability of PET imaging lie in the radiopharmaceutical used, among other factors; however, in general, PET has a much higher spatial resolution than conventional scintigraphy images [ 53 ].

PET/CT with choline analogs has shown higher sensitivity and specificity in detecting prostate bone metastases than BS, which can be explained by the optimal detection of bone marrow involvement and its ability to monitor cell proliferation compared with 18 F-NaF-PET [ 56 ].

Lipid metabolism in bone metastases varies according to the type of lesion; thus, less sclerotic lesions exhibit greater metabolic activity. These findings led to the establishment of the hypothesis that hypometabolic sclerosing lesions reflect reparative bone changes, whereas hypermetabolic lesions with no significant increase in radiological density are related to spinal or microsclerotic metastases in which cellularity and tumor replication, generally present in the early stages of the lesion, are greater than reparative bone activity [ 57 ].

More recently, PET/CT with PSMA, labeled with 68 Ga or 18 F, has shown a higher SE in the detection of bone disease [ 58 – 60 ]; however, there is little evidence of its yield. The most relevant study in which PSMA-PET/CT or PET/MRI was compared with BS in 37 patients showed sensitivity values of 100 and 57% for 68 Ga-PSMA-PET/CT and BS, respectively, with comparable specificity values (100 vs. 96%, respectively) [ 61 ]. Table 2 shows the most important differences between the main PET radiopharmaceuticals used in clinical practice. Table 2 Positive and negative aspects of the main PET radiopharmaceuticals used in clinical practice for the detection of metastatic bone disease Radiopharmaceutical Target Strengths Weaknesses 18 F-FDG Cellular glucose metabolism Glycolytic activity allows identification of lesions with aggressive tumor biology Low diagnostic yield in prostate cancer due to low affinity for glucose 18 F-Choline Cellular membrane proliferation Allows the identification of bone and soft tissue lesions Limited sensitivity for the detection of liver lesions 68 Ga or 18 F-PSMA Cell membrane protein expressed in prostate carcinoma Identifies bone lesions and lymph node involvement at less elevated PSA values and PSA doubling time Little bibliographic evidence on the real impact on survival, PSMA expression is increased in patients on antiandrogenic therapy 18 F-NaF Bone remodeling High sensitivity for the detection of bone metastases Does not allow visualization of extraosseous lesions 18 F-FDG [18F] 2-fluoro-2- d -glucose, 18 F-NaF 18F-sodium-fluoride, PSA prostatic specific antigen, PSMA prostate-specific membrane antigen

18 F-FDG-PET

18 F-FDG is the most universally widespread oncotropic radiopharmaceutical; its deposition is related to tumor glycolytic activity, making it a direct measure of cell viability and tumor cell biology. Its high availability and its ability to quantify metabolic activity as an indispensable parameter for the evaluation of the response to therapy are its main advantages [ 26 , 62 ]. However, this imaging modality is not without disadvantages, which are especially evident in certain scenarios. The tumor affinity for FDG and, therefore, the diagnostic yield and SE of the test depend on the tumor histological type in many cases [ 63 ]; thus, well-differentiated neoplasms and indolent tumors with a low mitotic rate or low aggressiveness can go unnoticed with FDG-PET imaging. Similarly, sclerosing bone metastases tend to have a lower glycolytic rate than purely lytic lesions or mixed lesions presumably due to the greater aggressiveness of the latter. In any case, a global sensitivity and specificity for detecting bone metastases of 98 and 56%, respectively, have been reported [ 26 ]: the specificity increases to 97% when combined with CT in hybrid PET/CT images [ 64 ].

Based on current evidence, routine FDG-PET/CT imaging is not recommended in patients with early-stage breast carcinoma (I or II) unless there are signs or symptoms of distant disease [ 65 – 68 ]; however, there is a sufficient level of evidence that supports its use in the initial staging of advanced-stage disease (level of evidence IA) based on an improvement in regional and distal staging.

18 F-NaF-PET

The main osteotropic radioisotope used for the acquisition of PET images is 18 F-NaF, which has a higher extraction rate than 99m Tc-HDP, with threefold higher plasma extraction in bone metastases compared with adjacent normal bone. After diffusion through the capillary wall into the extracellular space, the fluoride ions undergo a gradual exchange with the hydroxyl groups of hydroxyapatite crystals to form fluorapatite and then deposit on the bone surface where remodeling is maximal [ 26 ].

Compared to other functional imaging modalities, NaF-PET has demonstrated a sensitivity and specificity clearly superior to those for bone scanning with 99m Tc-HDP for the detection of metastasis, especially of the lytic type [ 35 , 63 ], and superior to that for FDG-PET, especially for sclerotic lesions [ 69 ]. Global sensitivity and specificity values of 100 and 97%, respectively, have been reported if hybrid PET/CT images are used [ 26 ].

The weaknesses of NaF-PET are similar to those of bone scanning and are mainly based on the high increase in bone remodeling in certain benign lesions and posttraumatic and infectious lesions.

Role of imaging techniques in the therapeutic monitoring of bone metastasis

1. Evaluation of the response of bone metastases in breast cancer

Bone metastases are the most common metastases in breast cancer. These metastases are most often osteolytic, but blastic metastases predominate in up to 20% of cases. Each predominant pattern is related to a different molecular mechanism at the level of the tumor cells in the bone marrow. Although it may be the initial form of presentation, the mixed pattern is typically more frequently observed during therapeutic follow-up when sclerosis of the metastases occurs with good response to treatment. There are no clinical, analytical or imaging diagnostic methods that predict which patients will develop metastatic bone disease; therefore, in late detection, the disease volumes and mutational heterogeneity are greater, requiring more toxic systemic therapies than in earlier disease stages [ 49 ]. Additionally, a greater metastatic bone disease volume is associated with reduced overall survival [ 70 ]. In addition, current clinical guidelines specify few recommendations for detecting of bone metastases in patients with advanced breast cancer and do not recognize the poor sensitivity of bone scintigraphy and CT [ 71 , 72 ].

Computed tomography

In general, the role of CT in the therapeutic monitoring of bone metastases is controversial. Bone metastases confined to bone are not considered measurable target lesions for RECIST unless there is a measurable soft tissue component [ 73 ]. Therefore, RECIST v1.1 shows limitations in the determination of the presence of bone metastasis and in the quantification of tumor load. In the specific setting of follow-up of breast cancer metastases, although CT is used in many clinical trials to assess response to treatment where there is a measurable soft tissue component, this technique shows important limitations [ 49 ]. In general, in most of the bone metastases imaging response criteria, and specifically in the one developed at the MD Anderson Cancer Center, the development of sclerosis in bone metastases is considered to be a sign of response to treatment [ 74 ]. Therefore, these same criteria do not consider that there is a progression in the case of the development of new osteosclerotic lesions if there are no other associated signs of progression. Specifically, in breast cancer bone metastases, lytic changes suggest that the progression and development of sclerosis is linked to improvement of metastatic disease, but sclerosis can also be found in cases of progression [ 75 ]. In addition, the MD Anderson Cancer Center criteria do not include references for tomodensitometry measurements of bone lesions; therefore, patients under treatment with bisphosphonates cannot be assessed by these criteria, as this kind of therapy suppresses osteoclast activity and increases bone mineral density. Finally, CT does not assess the heterogeneity of the response and shows limitations in the evaluation of early responses or resistance to treatment.

The use of dual or spectral energy CT allows the generation of a bone-iodine separated set of images and can be used to detect bone metastases with greater sensitivity [ 36 ] and better characterize bone lesions in oncological patients [ 76 ]. However, data on its potential role in therapeutic follow-up are lacking. Furthermore, the use of bone subtraction maps has been proposed to increase the accuracy and efficiency of CT in the therapeutic monitoring of pelvic breast cancer metastases [ 77 ].

Diffusion-weighted WB-MRI

The follow-up of patients with bone metastases undergoing treatment is typically performed with CT, 18 FDG PET/CT or bone scintigraphy. CT and bone scintigraphy only allow assessing whether patients are stable or have worsened but not whether they have improved in an objective and quantifiable way [ 32 ]. Criteria for progression and regression of bone metastases were defined with morphological MRI sequences [ 78 ] (Table 3 ). However, there are few clinical data supporting the use of structural sequences to evaluate therapeutic responses. Other limitations in the assessment of responses with morphological sequences are related to the presence of sclerosis, fibrosis or diffuse bone necrosis that usually occurs after several treatment cycles, making it difficult to determine the presence of new lesions and changes in the lesions that are being treated. Another confounding factor is the phenomenon of pseudoprogression in T1-weighted sequences, which produces a diffuse decrease in the bone signal due to diffuse bone edema secondary to massive cell death and inflammation, which can be confused with progression [ 49 ]. Table 3 MRI morphological criteria of bone metastasis progression and regression Progression criteria Regression criteria New focal lesion or area of diffuse metastatic infiltration in the bone marrow Disappearance of a focal lesion or area of diffuse metastatic infiltration in the bone marrow Increase in the size or number of focal lesions Decrease in the size or number of focal lesions Evolution of focal lesions to a diffuse neoplastic pattern Decrease in the extension of a diffuse neoplastic pattern Appearance of intra- or peritumoral fat (fat dot and halo signs) Decrease in contrast enhancement Development of dense sclerosis with well-defined or thin margins Disappearance of the hyperintense perilesional ring in fat-suppressed T2-weighted sequences

In the evaluation of therapeutic responses, the use of diffusion-weighted sequences and ADC quantifications is much more interesting. An appropriate therapeutic response is generally associated with an increase in the ADC related to cytotoxicity, decreased cellularity and loss of cell membrane integrity. However, this response may vary depending on the type of therapy and the time since the start of treatment [ 32 ] (Table 4 ). ADC measures have shown adequate repeatability and allow the detection of variations greater than 12% related to treatment; therefore, they are an adequate biomarker to detect the changes produced by therapy [ 79 ]. In addition, WB-MRI, particularly the diffusion-weighted sequence, allows determination of the tumor load and the individual changes induced by therapy through ADC measures. This information allows differentiation between stable, responsive and nonresponsive patients, including in the final stages of the disease when the aforementioned fibrotic changes occur in the bone marrow (Fig. 2 ). Additionally, DWI allows the evaluation of heterogeneous response patterns to treatment, which are usually produced when the metastases are derived from different cell clones [ 32 ]. Table 4 Patterns of responses to therapy for bone metastases evaluated with diffusion-weighted sequences and apparent diffusion coefficients Response patterns Meaning Increase in the volume, appearance of new areas or increase in the signal intensity of abnormal areas with high b values Progression The ADC may increase, remain stable or show a slight decrease No changes in lesions with high b values Response Marked ADC increase (T2 shine-through) Decrease in the signal intensity in abnormal areas with high b values Response Significant increase in the ADC: varies according to the type of treatment and changes that occur in the bone marrow No changes in lesions with high b values Stability ADC stable or slight (not significant) decrease or increase Decrease in the signal intensity of lesions detected with high b values Undetermined a Decrease in ADC ADC apparent diffusion coefficient a This pattern is usually visualized when sclerosis or myelofibrosis develops in the bone marrow or when there is an increase in the fatty bone marrow. This pattern is more common in responders but can occur in cases of sclerotic progression. When it occurs, the response must be evaluated based on morphological sequences Fig. 2 A 77-year-old patient with breast cancer presented with diffuse bone metastatic involvement in the initial staging with diffusion whole-body MRI ( A , left) with a heterogeneous response at 6 months ( B , center) given progression of pelvic, lumbar, and lower dorsal and costal bone disease and partial response of metastatic disease in middle and upper dorsal bodies and shoulder girdle. At the 3-month follow-up ( C , right), we found a marked progression of bone disease of the generalized form

Among WB imaging techniques, diffusion-weighted WB-MRI offers the greatest capabilities for evaluating the therapeutic response of bone metastases from breast cancer. This is the only technique along with 18 FDG-PET/CT that allows direct evaluation of the viability of tumor cells in the bone marrow. Clinical guidelines recommend the use of clinical assessment, tumor markers and CT and bone scintigraphy as imaging methods and only recognize an optional role for 18 FDG-PET/CT; they do not consider WB-MRI [ 71 , 80 ]. However, WB-MRI with morphological sequences, such as 18 FDG-PET/CT, presents problems in detecting tumor activity in bone if a healing process has developed in the bone marrow via previous therapies, if there is bone marrow hyperplasia (for example, by colony-stimulating factors) or if there is sclerotic progression. In this sense, recent data support the reliability of morphological MRI sequences to determine whether there is progression or stability; however, there are limitations to determining whether there is a disease response [ 81 ]. However, these limitations can be overcome with the use of diffusion-weighted sequences with ADC measures, as demonstrated by another recent series that compared the efficacy of CT and diffusion-weighted WB-MRI for the evaluation of systemic response to therapy in 101 patients with breast cancer with bone metastases. WB-MRI detected additional sites of distant disease in 53.3% of the patients. In addition, WB-MRI classified 65.5% of cases as a progression that were labeled stable disease on CT, mainly in patients under treatment with second-line drugs. Therapy was modified in 35% of the cases due to diffusion-weighted WB-MRI findings [ 82 ]. Finally, a recent prospective study in 45 patients with bone-only metastatic breast cancer confirmed the superior performance of WB-MRI in therapy monitoring, as progressive disease was evident in only half of participants at bone scintigraphy compared to WB-MRI, and it also enabled identification of progressive disease before CT in most patients [ 83 ].

Therefore, diffusion-weighted WB-MRI provides the opportunity for early detection of the presence of distant bone disease, allows assessing the heterogeneity in response to targeted therapies and identifies patients who do not benefit from a line of treatment at an early stage after its establishment [ 32 ]. Although sufficient data to systematically endorse the use of diffusion-weighted WB-MRI in the management of breast cancer is lacking, its use in certain scenarios is beneficial (Table 5 ). Table 5 Potential clinical scenarios in breast cancer patients where diffusion-weighted MRI could be applied Equivocal findings in scintigraphy or CT Differentiation between metastatic and osteoporotic fracture Exclude bone metastases in patients with low suspicion of bone disease Staging of patients with high-risk breast cancer at diagnosis a Substitute for CT or 18 FDG-PET/CT in patients with early locoregional recurrence Determining the extent of the disease in therapy monitoring Detection of oligometastatic disease that is a candidate for local treatment Evaluation of locally advanced breast carcinoma Evaluation of local recurrence Assessment of metastatic bone disease and/or hepatic disease treated with systemic therapy CT computed tomography, 18 FDG-PET/CT 18-fluorodeoxyglucose-positron emission tomography/computed tomography a High-risk patients are considered those with inoperable locally advanced breast cancer, inflammatory cancer, breast cancer diagnosed during pregnancy, cancer with more than four positive nodes, or triple-negative breast cancer

Bone scintigraphy

BS with 99m Tc-HDP is indicated and included in the different clinical guidelines in the initial staging of breast carcinoma from stage IIb (level of evidence 2B) and whenever there is clinical justification regardless of the stage [ 84 – 86 ]. However, after the onset of systemic therapy, changes in response may not be detectable by scintigraphy or may take up to 6 months to be reflected in approximately 50% of responding patients [ 49 , 87 ]. This finding is attributed to the fact that scintigraphy manifests peritumoral bone structural alterations but does not directly represent tumor cellular activity. A paradoxical response defined as a “flare” phenomenon, which is characterized by a greater osteoblast reaction in known lesions or even the appearance of “new lesions”, can also be observed after therapy as a translation of reparative osteogenic response in preexisting lesions that are predominantly lytic. Finally, in some cases, a decrease in uptake can be observed in rapidly progressive disease due to massive destruction without reparative osteoblastic activity, but this response is uncommon. This decrease in uptake intensity can be misinterpreted as a response to treatment [ 88 ].

In addition, certain chemotherapy regimens can directly interfere with bone remodeling. For example, denosumab, an anti-RANKL monoclonal IgG2 antibody, inhibits osteoclast function [ 89 ], interfering with the evaluation of response in bone scans and simulating a correct response of metastatic disease.

Certain limitations of scintigraphic images could be partially solved when evaluating the response to treatment by applying the most recent technological advances, such as the quantification of tumor load (percentage of total skeletal mass), quantitative normalization of the uptake intensity and segmentation of bone uptake compared to healthy controls [ 89 ]. However, this technology is not yet applicable in daily clinical practice. Similarly, hybrid SPECT/CT imaging facilitates the characterization of doubtful lesions in planar imaging as well as the identification of lytic lesions and their sclerotic transformation in responding patients.

In any case, the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) has discouraged the use of BS as a tool for the evaluation of responses: "there is no evidence that bone scintigraphy can be used to evaluate the response to treatment" [ 84 ]. Therefore, its use in this scenario is not recommended.

BS should be used only when there is suspicion of progression, in which case 2 new lesions should be documented after the “flare-up” period (first 12 weeks) with a lapse of at least 6 weeks [ 26 , 49 , 89 ]. BS should not be used for the assessment of response to treatment due to the risk of erroneous image interpretation.

The specific bone response criteria proposed by MD Anderson Cancer Center in 2004 combine radiological findings (conventional radiography, CT, and MRI) with BS findings. The criteria propose response stratification through qualitative evaluation of scintigraphy. Thus, complete normalization of the uptake of labeled diphosphonates translates into a complete response, a subjective decrease in uptake ≥ 50% into a partial response, and a subjective increase ≥ 25% or the appearance of new lesions into disease progression [ 90 ].

Positron emission tomography

18 F-NaF-PET

Although the absorption of 18 F-fluoride depends on regional blood flow and osteoblastic activity, similar to 99m Tc-HDP, the increased spatial resolution of PET imaging, higher lesion/background uptake ratio and better visualization of lesions located in bone marrow make 18 F-NaF-PET a more sensitive bone imaging modality for the detection of metastatic, blastic and even lytic lesions and for the evaluation of response to treatment [ 31 , 91 ]. However, its reduced availability and increased cost hinder its use in routine clinical practice.

18 F-FDG-PET/TC

As an oncotropic radiopharmaceutical, 18 F-FDG provides direct information on tumor cell viability in metastatic lesion beds. However, the SE of the technique for the detection of secondary bone disease is directly influenced by certain factors specific to tumor biology, especially the immunohistochemical phenotype. Thus, semiquantitative metabolic parameters, such as the standardized uptake value (SUVmax), are clearly superior in biologically more aggressive neoplasias (high-grade, negative for hormonal receptors, HER2-positive or triple-negative cancers) compared with those that exhibit less aggressive tumor biology [ 92 , 93 ].

Some chemotherapeutic agents produce cytostatic rather than cytolytic effects in tumor cells, controlling the disease without an apparent reduction in the size of the lesion and hindering the assessment of response based exclusively on morphological or volumetric criteria. The regular and well-defined tumor margins necessary for a reproducible radiological measurement are of less importance in functional imaging [ 94 ].

After initiating systemic therapy, FDG-PET can only be useful in evaluating response in patients with previous positive metabolic studies. Although it is not systematically indicated in the current international guidelines to evaluate the response of metastatic disease, an important potential advantage has been demonstrated over conventional imaging, with an excellent symptom/image concordance rate in patients with disease resolution or improvement [ 95 ] (Fig. 3 ). Although the persistence of focal hypermetabolism can demonstrate residual uptake after effective therapy that is probably related to macrophage activity, this feature often translates to uncontrolled disease. In contrast, the resolution of glycolytic activity indicates disease control, regardless of the appearance of the lesion on BS (often persistently positive) or its radiological appearance on the CT component of PET/CT [ 88 ]. Fig. 3 Added value of PET/CT in the characterization of treated secondary bone lesions. A 53-year-old woman, diagnosed with infiltrating ductal breast carcinoma, treated with surgery, chemotherapy, and radiotherapy. Bone scintigraphy and CT showed osteoblastic lesions suspicious for metastases that did not respond to treatment. In this scenario, FDG-PET/CT image makes it possible to rule out signs of tumor viability in skeletal lesions, classifying them as old lesions with a complete response to treatment

Another scenario in which hybrid images can clarify the situation of metastatic disease is the "flare" reaction, which is observed as a generalized increase in the metabolic activity in the bone marrow after the use of granulocyte colony-stimulating factor and is very intense in some cases. This confounding factor in PET images has been described 7–10 days after initiation of tamoxifen or fulvestrant therapy for breast cancers with positive hormone receptors, which may indicate the success of the therapy [ 96 ].

Different quantitative criteria have been designed to assess the response to systemic therapy, such as those of the European Organization for Research and Treatment of Cancer (EORTC) and the more recent and standardized PET Response Criteria in Solid Tumors (PERCIST), which allow stratification of the response according to the percentage change in activity in the most active lesion between the pre- and post-treatment studies (Table 6 ). Table 6 Criteria for the assessment of metabolic response EORTC PERCIST Target lesion The defined pretreatment tumor region must correspond to the increased uptake of 18 F-FDG (viable tumor) Those who present an SULpeak of at least 1.5 times that calculated in the liver. If there is liver pathology, then it must be at least two times higher than a vascular ROI in the thoracic descending aorta Quantification of five measurable target lesions (no more than two lesions per organ) Complete metabolic response Normalization of the uptake of 18 F-FDG in the tumor volume with indistinguishable activity of the surrounding healthy tissue Complete disappearance of the pathological uptake of 18 F-FDG in all lesions (target and nontarget) that have activity lower than hepatic activity and are indistinguishable from the vascular background Verification in 1 month if there is anatomical criterion of progression Partial metabolic response Reduction of between 15 and 25% of the SUV of the tumor after 1 chemotherapy cycle and > 25% after more than 1 cycle Reduction of at least 30% in SULpeak in target lesions Verification in a follow-up study if there is an anatomical criterion of progression Stable disease Increase < 25% or reduction < 15% in SUV without an increase in the extent of uptake (< 20% of the largest dimension) No complete or partial metabolic response or metabolic progression Metabolic progression SUV increase > 25%. Increase > 20% in the extension of uptake. Appearance of new pathological uptake of 18F-FDG Increase in SULpeak > 30% in target lesions. Increase in the extent of uptake (> 75% in total lesion glycolysis, or TLG). Emergence of new pathological uptake of 18F-FDG not explainable by treatment or infection effects Verification in a follow-up study if there is an anatomical criterion of partial or complete response EORTC European Organization for Research and Treatment of Cancer, PERCIST Positron Emission tomography Response Criteria In Solid Tumors, ROI region of interest, SUV standardized uptake value, SUL standardized uptake value corrected for lean body mass, 18F-FDG [18F] 2-fluoro-2- d -glucose

Although an almost perfect correlation between both response criteria has been demonstrated [ 97 ], the EORTC uses SUVmax as a variable, whereas PERCIST proposes the use of the SUV corrected for lean body mass (SULpeak) as a normalization tool to decrease fat tissue as a confounder [ 98 , 99 ].

The modified RECIST v1.1 criteria consider the metabolic behavior of the lesion as one of the variables of interest; however, this is only considered for the detection of tumor progression providing that the findings in functional images accompany a radiological correlate or show metabolic progression over time or are demonstrated in a subsequent radiological study [ 73 ].

Specific radiopharmaceuticals for breast cancer

Specific oncotropic radiopharmaceuticals, such as 18 F-fluoroestradiol (FES-PET), have demonstrated the ability to identify patients responding to treatment earlier than FDG-PET only 7–10 days after starting treatment with tamoxifen; these processes also facilitate correct selection of candidate patients for treatment. The use of FES-PET can increase the overall response rate from 23 to 34%. For patients with HER2/neu-negative breast carcinoma, the response to treatment can increase from 29 to 46% if the patient selection has been performed with FES-PET [ 55 ].

Specific radiopharmaceuticals for human epidermal growth factor 2 (HER2) allow the characterization of lesions by determining the expression of HER2 in the primary lesion and metastatic lesions with PET and facilitating the correct selection of candidate patients for targeted therapy. Similarly, radiopharmaceuticals for radiometabolic therapy directed against HER2 (theragnosis) have been designed and applied in the preclinical setting [ 100 , 101 ]. 2. Evaluation of the response of bone metastases in prostate cancer

Bone metastasis occurs in up to 62% of patients with newly diagnosed metastatic PCa and in greater than 40% of patients with castration-resistant prostate cancer (CRPCa) [ 27 ]. In addition, the volume of metastatic bone disease is an independent prognostic factor in patients with PCa [ 102 ]. Furthermore, it is especially important to detect oligometastatic disease (in initial staging, recurrence or progression), which is defined as five or fewer metastatic lesions (intermediate situation between localized and disseminated disease), because this scenario may require radical locoregional management, allowing the prevention of or delay in the spread of the disease and initiation of a specific therapy.

The current diagnostic pathway for metastatic PCa is based on the presence of symptoms, prostate-specific antigen (PSA) levels and the combination of scintigraphy and CT. Thus, in the castration-sensitive phase, the assessment is based on the presence or absence of symptoms and PSA levels. The role of imaging is typically focused on determining the initial tumor load and its changes in cases of response or progression. However, in CRPCa, imaging follow-up with the use of new therapies is recommended. For example, between 21 and 30% of patients under treatment with abiraterone or enzalutamide without clinical signs or elevated PSA levels develop radiological progression, and 40% of patients with bone involvement under treatment with Ra 223 alone develop visceral progression [ 103 ].

The most commonly measured serum marker, PSA, has obvious limitations, such as the possibility of radiological progression without elevation of this marker. New serum biomarkers, such as circulating tumor cells, have shown promising results but cannot be considered conclusive with poor correlations with the response as evaluated by CT or PET [ 27 ]. In this manner, new imaging modalities may contribute to the improved management of advanced prostate carcinoma by defining the presence and extent of tumors as well as the correct and early evaluation of response to treatment.

Computed tomography

CT evaluates the soft tissue response following the RECIST v1.1 criteria and allows the determination of response, progression, or stability. However, it presents apparent limitations in the evaluation of the response of bone disease; for example, the appearance of new sclerotic lesions cannot be considered, per se, a criterion of progression [ 32 ]. Both CT and scintigraphy present difficulties in assessing the heterogeneity of response to treatment of local and distant disease [ 104 ].

Diffusion-weighted WB-MRI

The advantages of the use of diffusion-weighted WB-MRI in the therapeutic monitoring of metastatic bone disease have already been discussed in the previous sections. The use of diffusion-weighted WB-MRI is not yet included in the assessment of high-risk PCa by the European Association of Urology (UAE) guidelines; however, the European Organization for Cancer Research and Treatment (EORTC) does recommend its inclusion in the diagnostic algorithm of PCa to identify oligometastatic disease and assess the response to treatment of metastases [ 105 ]. Furthermore, the Metastasis Reporting and Data System for Prostate Cancer (MET-RADS-P) guidelines have been published to improve reproducibility in the acquisition, comparison and reading of WB-MRI for the evaluation of metastatic PCa [ 106 ]. In CRPC patients, the use of this staging system has confirmed that the extent of bone metastases and the presence of visceral lesions are associated with shorter cancer-specific survival. These initial results open the door to using the MET-RADS-P score as a prognostic imaging biomarker for CRPC [ 107 ].

This technique is not affected by the “flare” effect of bone scintigraphy, allowing a quantitative and more reliable determination of the metastatic tumor load, which has prognostic implications and minimizes the use of ineffective therapies in patients with a low tumor load. Another field of application is the improvement in the detection of oligometastatic disease, allowing local rather than systemic treatments in this group of patients. Especially relevant is the more accurate and early detection of changes induced by therapy, introducing the possibility of differentiating between response, progression and stability, which improves the stratification of patients and therapeutic selection and, expectedly, final patient outcomes [ 32 ]. In this sense, quantitative biomarkers derived from diffusion-weighted sequences, such as ADC measures and tumor volume measured by means of DWI, correlate with serum biomarkers and clinical response to olaparib (inhibitor of the poly ADP-ribose polymerase enzyme) in patients with advanced PCa [ 108 ]. Another field of development for diffusion-weighted WB-MRI is the evaluation of tumor heterogeneity, an important factor in the response to therapy and in the development of resistance to treatment. Finally, this technique opens the possibility of conducting imaging biopsies to improve the understanding of the mechanisms of resistance to treatment by categorizing the genetic and molecular profiles of metastatic PCa and improving therapeutic selection [ 27 ].

Bone scintigraphy

BS with 99m Tc-HDP is the most commonly used method to evaluate metastatic bone disease in patients with PCa as part of the validated criteria of the Prostate Cancer Working Group 3 to detect progression after treatment [ 109 ]. A meta-analysis with 1102 patients studied using planar BS and SPECT yielded combined sensitivity and specificity values to detect bone metastases of 79 and 82%, respectively [ 43 ]. The scintigraphic progression criterion requires the identification of at least two new bone lesions in consecutive studies. If detected, new lesions should be confirmed in a subsequent BS performed after at least 6 weeks to exclude the possible “flare” effect [ 109 ].

Positron emission tomography

The usefulness of 18 F-FDG-PET in prostate cancer is directly related to the phase of the disease. However, globally, it has a low yield due to poor avidity for glucose in prostate tumor cells, and the low uptake in metastatic lesions tends to decrease with androgen deprivation therapy or chemotherapy. However, tumors with more aggressive tumor biology than a Gleason score > 7 (clinically significant PCa) tend to have a high glycolytic rate [ 110 ].

In any case, PET with choline analogs has shown a higher rate of identification of tumor recurrence (58%) in both prostatic, lymphatic and bone bed lesions with an overall sensitivity and specificity of 86 and 93%, respectively [ 111 ].

Regarding the assessment of response to treatment, 18 F, 11 C-choline, 68 Ga or 18 F-PSMA offer the advantage of simultaneously evaluating the response of soft tissue and bone involvement, detecting signs of progression before CT and BS and obtaining a correlation between the decrease in SUV and overall survival.

In a recent study conducted in 177 patients with prostate cancer and 443 metastatic bone lesions and aimed at assessing the response of bone metastases by CT and PSMA-PET volumetric parameters: whole-body total-lesion PSMA, whole-body PSMA-tumor volume, as well as the established maximum standard uptake values (SUVmax) and mean standard uptake values (SUVmean), an association was determined between SUVmean, Gleason Scores, lesion classification, and serum-PSA levels but not for CT-derived bone density measurements before and after therapy ( p > 0.05). Additionally, a highly significant correlation was observed for changes in PSMA-tumor volume, whole-body total-lesion PSMA, and serum PSA levels ( p < 0.001) [ 112 ].

Perspectives for the future

Currently, imaging techniques can provide quantitative information on the structural, functional and molecular aspects of cancer. Multiple quantitative biomarkers are derived from their processing, which allows studying new aspects of tumor biology, such as heterogeneity. The set of multivariate analysis techniques for these imaging biomarkers to detect new diagnostic, prognostic or predictive information on the response to treatment is called radiomics and has begun to be used in the evaluation of bone metastases. Thus, radiomics allows the successful differentiation between metastatic and nonmetastatic vertebral lesions in oncological patients investigated with MRI [ 113 ] and, more interestingly, allows prediction of the risk of metastatic bone disease in PCa using MRI texture analysis of the primary tumor [ 114 ].

Both in the therapeutic spectrum and in what concerns us now, namely, diagnosis, the development of nuclear medicine is fundamentally aimed at the synthesis of new radiopharmaceuticals with radiotherapeutic capacity and with greater and more selective affinity to the tumoral tissue under study, all to apply a personalized methodology to each histological phenotype.

In addition, the new diagnostic focus has been combined in recent years with the use of hybrid SPECT/CT, PET/CT and, more recently, PET/MRI. In addition to offering the possibility of integrating the functional/molecular information of PET in a single acquisition with the high-resolution anatomical information of MRI together with the functional information proportionated by DWI, this last modality could provide new and unique information additional to that obtained through the different PET radiotracers [ 115 ].

The radiopharmaceutical used in most PET/MRI studies is 18 F-FDG, showing a greater SE in a group of 109 patients than that for 18 F-FDG-PET/CT in the detection of bone metastasis in breast cancer (96 and 85%, respectively) with an SP of 99% [ 116 , 117 ]. In addition, PET/MRI showed a greater number of bone metastases than PET/CT in 67 cancer patients with different tumor cell lines [ 115 ]. However, the SE of the technique is associated with the radiopharmaceutical used; therefore, new advances are directed to the application of new PET/MRI radiopharmaceuticals with favorable pharmacokinetic characteristics. Additionally, the use of 18 FDG PET-MRI for staging breast cancer patients at high risk for metastases results in a treatment regimen in 14% of patients compared to a traditional staging imaging algorithm (including X-ray mammography, breast ultrasonography, chest plain radiography, bone scintigraphy, and ultrasonography of the liver and axillary fossa) [ 118 ].

Another study has shown a moderate but significant inverse correlation between increased choline metabolism and ADC values of bone metastases from prostate cancer using 8 F-choline-PET/MRI [ 119 ]. In addition, Na[ 18 F]F/[ 18 F]FDG-PET/MRI permits the identification of more skeletal lesions than bone scintigraphy and the additional identification of extraskeletal disease in breast and prostate cancer patients [ 120 ].

68 Ga-PSMA-PET/MRI scans show a high detection rate of prostate cancer recurrence even at very low PSA levels (< 0.5 ng/mL). In addition, at these levels, extrapelvic disease can be detected in 25% of cases [ 121 ]. In addition, recent data support that limited pelvic PSMA-PET/MR is equivalent to PET/CT in the assessment of metastatic regional lymph nodes and bone lesions and is superior to PET/CT with regard to capsular invasion and seminal vesicle involvement [ 122 ].

Despite these promising results, PET/MRI continues to be a technique with low accessibility due to its cost and the limited availability of hybrid equipment.

Conclusions

Unfortunately, the metastatic bone disease remains a common clinical problem, particularly in patients with breast and prostate cancers. Classical imaging techniques, such as CT and bone scanning, have shown limited sensitivity in the detection and, more importantly, in the response assessment of these entities. Recent results support the use of next-generation imaging techniques, including whole-body diffusion-weighted MRI, PET/CT and PET/MRI with novel radiopharmaceuticals instead of the classic combination of CT and bone scans, due to improved results in detection, staging and categorization of the response to local and systemic therapies. In a practical example of precision and personalized medicine, the use of next-generation imaging technologies in patients with metastatic bone disease combined with information from other genetic and molecular diagnostic techniques, which offer complementary capacities, offers clinicians a wide armamentarium of diagnostic, predictive and prognostic biomarkers to improve patient management and outcome.

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Acknowledgements

The authors would like to thank to Fernando Rico-Villademoros (COCIENTE SL, Madrid, Spain) for editorial assistance in the preparation of this manuscript. His participation has been funded by the participating scientific societies.

Author contributions

Conception and design: JOR, JMS, ALA. Manuscript writing: all authors. Final approval of manuscript: all authors. Accountable for all aspects of the work: all authors.

Funding

Spanish Society of Medical Oncology (SEOM), the Spanish Society of Medical Radiology (SERAM), and Spanish Society of Nuclear Medicine and Molecular Imaging (SEMNIM) equally funded this consensus.

Availability of data and material

Not applicable.

Declarations

Conflict of interest

JMS-S is member of the advisory board for MSD and Abbvie and has received research grants to institution from Pfizer and has received travel grants from Ipsen. AL has received lecturer honorarium from Philips Healthcare and Canon. JOR, MM, JM-L, GF-P, EN, SS-V and JCV report no conflict of interest.

Ethical approval

The manuscript does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent/ethical approval is not required for this type of project.

Code availability

Not applicable.

References

1. Coleman RE Clinical features of metastatic bone disease and risk of skeletal morbidity Clin Cancer Res 2006 12 6243s 6249s 10.1158/1078-0432.CCR-06-0931 17062708

2. Amelot A Terrier LM Le Nail LR Cristini J Cook AR Buffenoir K Pascal-Moussellard H Carpentier A Dubory A Mathon B Spine metastasis in patients with prostate cancer: survival prognosis assessment Prostate 2021 81 91 101 10.1002/pros.24084 33064325

3. Jemal A Siegel R Xu J Ward E Cancer statistics, 2010 CA Cancer J Clin 2010 60 277 300 10.3322/caac.20073 20610543

4. Reddington JA Mendez GA Ching A Kubicky CD Klimo P Jr Ragel BT Imaging characteristic analysis of metastatic spine lesions from breast, prostate, lung, and renal cell carcinomas for surgical planning: osteolytic versus osteoblastic Surg Neurol Int 2016 7 S361 S365 10.4103/2152-7806.182549 27274410 PMC4879848

5. Kawai AT Martinez D Saltus CW Vassilev ZP Soriano-Gabarró M Kaye JA Incidence of skeletal-related events in patients with castration-resistant prostate cancer: an observational retrospective cohort study in the US Prostate Cancer 2019 2019 5971615 10.1155/2019/5971615 31360552 PMC6652049

6. Hong S Youk T Lee SJ Kim KM Vajdic CM Bone metastasis and skeletal-related events in patients with solid cancer: a Korean nationwide health insurance database study PLoS ONE 2020 15 e0234927 10.1371/journal.pone.0234927 32678818 PMC7367479

7. Roodman GD Mechanisms of bone metastasis N Engl J Med 2004 350 1655 1664 10.1056/NEJMra030831 15084698

8. Smerage JB Barlow WE Hortobagyi GN Winer EP Leyland-Jones B Srkalovic G Tejwani S Schott AF O'Rourke MA Lew DL Doyle GV Gralow JR Livingston RB Hayes DF Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500 J Clin Oncol 2014 32 3483 3489 10.1200/JCO.2014.56.2561 24888818 PMC4209100

9. Schellhammer PF Chodak G Whitmore JB Sims R Frohlich MW Kantoff PW Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial Urology 2013 81 1297 1302 10.1016/j.urology.2013.01.061 23582482

10. Ryan CJ Smith MR de Bono JS Molina A Logothetis CJ de Souza P Fizazi K Mainwaring P Piulats JM Ng S Carles J Mulders PF Basch E Small EJ Saad F Schrijvers D Van Poppel H Mukherjee SD Suttmann H Gerritsen WR Flaig TW George DJ Yu EY Efstathiou E Pantuck A Winquist E Higano CS Taplin ME Park Y Kheoh T Griffin T Scher HI Rathkopf DE Abiraterone in metastatic prostate cancer without previous chemotherapy N Engl J Med 2013 368 138 148 10.1056/NEJMoa1209096 23228172 PMC3683570

11. Crawford ED Stone NN Yu EY Koo PJ Freedland SJ Slovin SF Gomella LG Berger ER Keane TE Sieber P Shore ND Petrylak DP Challenges and recommendations for early identification of metastatic disease in prostate cancer Urology 2014 83 664 669 10.1016/j.urology.2013.10.026 24411213

12. Mottet N, Van den Bergh RCN, Briers E, Cornford P, De Santis M, Fanti S, Fossati N, Gandaglia G, Gillessen S, Grivas N, Grummet J, Henry AM, van der Kwast TH, Lam TB, Lardas M, Liew M, Mason MD, Moris L, Oprea-Lager DE, van der Poel HG, Rouvie`re O, Schoots IG, Tilki D, Wiegel T, Willemse P-PM, Cornford P. EAU-ESTRO-ESUR-SIOG 2019 guidelines on prostate cancer. 2019. https://uroweb.org/guideline/prostate-cancer/#5 . Accessed 12 Sept 2019.

13. Tosoian JJ Gorin MA Ross AE Pienta KJ Tran PT Schaeffer EM Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations Nat Rev Urol 2017 14 15 25 10.1038/nrurol.2016.175 27725639 PMC5808411

14. Trovo M Furlan C Polesel J Fiorica F Arcangeli S Giaj-Levra N Alongi F Del Conte A Militello L Muraro E Martorelli D Spazzapan S Berretta M Radical radiation therapy for oligometastatic breast cancer: results of a prospective phase II trial Radiother Oncol 2018 126 177 180 10.1016/j.radonc.2017.08.032 28943046

15. Palma DA Olson R Harrow S Gaede S Louie AV Haasbeek C Mulroy L Lock M Rodrigues GB Yaremko BP Schellenberg D Ahmad B Senthi S Swaminath A Kopek N Liu M Moore K Currie S Schlijper R Bauman GS Laba J Qu XM Warner A Senan S Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial J Clin Oncol 2020 38 2830 2838 10.1200/jco.20.00818 32484754 PMC7460150

16. Lattouf JB Saad F Preservation of bone health in prostate cancer Curr Opin Support Palliat Care 2007 1 192 197 10.1097/SPC.0b013e3282f0c74f 18685362

17. Hillengass J Usmani S Rajkumar SV Durie BGM Mateos MV Lonial S Joao C Anderson KC García-Sanz R Riva E Du J van de Donk N Berdeja JG Terpos E Zamagni E Kyle RA San Miguel J Goldschmidt H Giralt S Kumar S Raje N Ludwig H Ocio E Schots R Einsele H Schjesvold F Chen WM Abildgaard N Lipe BC Dytfeld D Wirk BM Drake M Cavo M Lahuerta JJ Lentzsch S International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders Lancet Oncol 2019 20 e302 e312 10.1016/s1470-2045(19)30309-2 31162104

18. Petralia G Padhani AR Pricolo P Zugni F Martinetti M Summers PE Grazioli L Colagrande S Giovagnoni A Bellomi M Whole-body magnetic resonance imaging (WB-MRI) in oncology: recommendations and key uses Radiol Med 2019 124 218 233 10.1007/s11547-018-0955-7 30430385

19. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. 2019. https://www.nccn.org/professionals/physician_gls/default.aspx . Accessed 23 Apr 2019.

20. Yu HM, Hoffe SE. Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults. UpToDate 2019. 2019. https://www.uptodate.com/contents/epidemiology-clinical-presentation-and-diagnosis-of-bone-metastasis-in-adults ? Accessed 12 Sept 2019.

21. Padhani AR Lecouvet FE Tunariu N Koh DM De Keyzer F Collins DJ Sala E Fanti S Vargas HA Petralia G Schlemmer HP Tombal B de Bono J Rationale for modernising imaging in advanced prostate cancer Eur Urol Focus 2017 3 223 239 10.1016/j.euf.2016.06.018 28753774

22. Bruckmann NM Kirchner J Morawitz J Umutlu L Herrmann K Bittner A-K Hoffmann O Mohrmann S Ingenwerth M Schaarschmidt BM Li Y Stang A Antoch G Sawicki LM Buchbender C Prospective comparison of CT and 18F-FDG PET/MRI in N and M staging of primary breast cancer patients: initial results PLoS ONE 2021 10.1371/journal.pone.0260804 34855886 PMC8638872

23. Choi J Raghavan M Diagnostic imaging and image-guided therapy of skeletal metastases Cancer Control J Moffitt Cancer Cent 2012 19 102 112 10.1177/107327481201900204 22487972

24. Yu HM, Hoffe SE. Overview of therapeutic approaches for adult patients with bone metastasis from solid tumors. UpToDate 2019. 2019. https://www.uptodate.com/contents/overview-of-therapeutic-approaches-for-adult-patients-with-bone-metastasis-from-solid-tumors ? . Accessed 12 Sept 2019.

25. von Moos R Lewis K Massey L Marongiu A Rider A Seesaghur A Initiation of bone-targeted agents in patients with bone metastases and breast or castrate-resistant prostate cancer actively treated in routine clinical practice in Europe Bone 2022 154 116243 10.1016/j.bone.2021.116243 34757213

26. O'Sullivan GJ Carty FL Cronin CG Imaging of bone metastasis: an update World J Radiol 2015 7 202 211 10.4329/wjr.v7.i8.202 26339464 PMC4553252

27. Perez-Lopez R Tunariu N Padhani AR Oyen WJG Fanti S Vargas HA Omlin A Morris MJ de Bono J Koh DM Imaging diagnosis and follow-up of advanced prostate cancer: clinical perspectives and state of the art Radiology 2019 292 273 286 10.1148/radiol.2019181931 31237493

28. Allan AL Vantyghem SA Tuck AB Chambers AF Tumor dormancy and cancer stem cells: implications for the biology and treatment of breast cancer metastasis Breast Dis 2006 26 87 98 10.3233/bd-2007-26108 17473368

29. Santini D Galluzzo S Zoccoli A Pantano F Fratto ME Vincenzi B Lombardi L Gucciardino C Silvestris N Riva E Rizzo S Russo A Maiello E Colucci G Tonini G New molecular targets in bone metastases Cancer Treat Rev 2010 36 Suppl 3 S6 10 10.1016/S0305-7372(10)70013-X 21129612

30. Lipton A Goessl C Clinical development of anti-RANKL therapies for treatment and prevention of bone metastasis Bone 2011 48 96 99 10.1016/j.bone.2010.10.161 20950721

31. Even-Sapir E Imaging of malignant bone involvement by morphologic, scintigraphic, and hybrid modalities J Nucl Med 2005 46 1356 1367 16085595

32. Padhani AR Makris A Gall P Collins DJ Tunariu N de Bono JS Therapy monitoring of skeletal metastases with whole-body diffusion MRI J Magn Reson Imaging 2014 39 1049 1078 10.1002/jmri.24548 24510426

33. Rybak LD Rosenthal DI Radiological imaging for the diagnosis of bone metastases Q J Nucl Med 2001 45 53 64 11456376

34. Karnholz R Sze G Current imaging in spinal metastatic disease Semin Oncol 1991 18 158 169 2014400

35. Yang HL Liu T Wang XM Xu Y Deng SM Diagnosis of bone metastases: a meta-analysis comparing (1)(8)FDG PET, CT, MRI and bone scintigraphy Eur Radiol 2011 21 2604 2617 10.1007/s00330-011-2221-4 21887484

36. Lee YH Kim S Lim D Suh JS Song HT Spectral parametric segmentation of contrast-enhanced dual-energy CT to detect bone metastasis: feasibility sensitivity study using whole-body bone scintigraphy Acta Radiol 2015 56 458 464 10.1177/0284185114530105 24714734

37. Buus TW Rasmussen F Nellemann HM Løgager V Jensen AB Hauerslev KR Christiansen P Pedersen EM Comparison of contrast-enhanced CT, dual-layer detector spectral CT, and whole-body MRI in suspected metastatic breast cancer: a prospective diagnostic accuracy study Eur Radiol 2021 31 8838 8849 10.1007/s00330-021-08041-2 34008104

38. Luna A Vilanova JC Alcala ML Total body MRI in early detection of bone metastasis and its indication in comparison to bone scan and other imaging techniques Arch Esp Urol 2015 68 371 390 25948807

39. Vilanova JC Baleato-Gonzalez S Romero MJ Carrascoso-Arranz J Luna A Assessment of musculoskeletal malignancies with functional MR imaging Magn Reson Imaging Clin N Am 2016 24 239 259 10.1016/j.mric.2015.08.006 26613884

40. Vilanova JC Garcia-Figueiras R Luna A Baleato-Gonzalez S Tomas X Narvaez JA Update on whole-body MRI in musculoskeletal applications Semin Musculoskelet Radiol 2019 23 312 323 10.1055/s-0039-1685540 31163505

41. Sun G Zhang YX Liu F Tu N Whole-body magnetic resonance imaging is superior to skeletal scintigraphy for the detection of bone metastatic tumors: a meta-analysis Eur Rev Med Pharmacol Sci 2020 24 7240 7252 10.26355/eurrev_202007_21879 32706062

42. Jambor I Kuisma A Ramadan S Huovinen R Sandell M Kajander S Kemppainen J Kauppila E Auren J Merisaari H Saunavaara J Noponen T Minn H Aronen HJ Seppanen M Prospective evaluation of planar bone scintigraphy, SPECT, SPECT/CT, 18F-NaF PET/CT and whole body 1.5T MRI, including DWI, for the detection of bone metastases in high risk breast and prostate cancer patients: SKELETA clinical trial Acta Oncol 2016 55 59 67 10.3109/0284186X.2015.1027411 25833330

43. Shen G Deng H Hu S Jia Z Comparison of choline-PET/CT, MRI, SPECT, and bone scintigraphy in the diagnosis of bone metastases in patients with prostate cancer: a meta-analysis Skeletal Radiol 2014 43 1503 1513 10.1007/s00256-014-1903-9 24841276

44. Sun W Li M Gu Y Sun Z Qiu Z Zhou Y Diagnostic value of whole-body DWI with background body suppression plus calculation of apparent diffusion coefficient at 3 T versus (18)F-FDG PET/CT for detection of bone metastases AJR Am J Roentgenol 2020 214 446 454 10.2214/ajr.19.21656 31799866

45. Wu LM Gu HY Zheng J Xu X Lin LH Deng X Zhang W Xu JR Diagnostic value of whole-body magnetic resonance imaging for bone metastases: a systematic review and meta-analysis J Magn Reson Imaging 2011 34 128 135 10.1002/jmri.22608 21618333

46. Morone M Bali MA Tunariu N Messiou C Blackledge M Grazioli L Koh DM Whole-body MRI: current applications in oncology AJR Am J Roentgenol 2017 209 W336 W349 10.2214/AJR.17.17984 28981354

47. Mohler JL Antonarakis ES Armstrong AJ D'Amico AV Davis BJ Dorff T Eastham JA Enke CA Farrington TA Higano CS Horwitz EM Hurwitz M Ippolito JE Kane CJ Kuettel MR Lang JM McKenney J Netto G Penson DF Plimack ER Pow-Sang JM Pugh TJ Richey S Roach M Rosenfeld S Schaeffer E Shabsigh A Small EJ Spratt DE Srinivas S Tward J Shead DA Freedman-Cass DA Prostate cancer, version 2.2019, NCCN clinical practice guidelines in oncology J Natl Compr Canc Netw 2019 17 479 505 10.6004/jnccn.2019.0023 31085757

48. Lecouvet FE El Mouedden J Collette L Coche E Danse E Jamar F Machiels JP Vande Berg B Omoumi P Tombal B Can whole-body magnetic resonance imaging with diffusion-weighted imaging replace Tc 99m bone scanning and computed tomography for single-step detection of metastases in patients with high-risk prostate cancer? Eur Urol 2012 62 68 75 10.1016/j.eururo.2012.02.020 22366187

49. Woolf DK Padhani AR Makris A Assessing response to treatment of bone metastases from breast cancer: what should be the standard of care? Ann Oncol 2015 26 1048 1057 10.1093/annonc/mdu558 25471332

50. Gnanasegaran G Cook G Adamson K Fogelman I Patterns, variants, artifacts, and pitfalls in conventional radionuclide bone imaging and SPECT/CT Semin Nucl Med 2009 39 380 395 10.1053/j.semnuclmed.2009.07.003 19801218

51. Zhang Y Zhao C Liu H Hou H Zhang H Multiple metastasis-like bone lesions in scintigraphic imaging J Biomed Biotechnol 2012 2012 957364 10.1155/2012/957364 22505821 PMC3312464

52. Cuccurullo V Cascini GL Tamburrini O Rotondo A Mansi L Bone metastases radiopharmaceuticals: an overview Curr Radiopharm 2013 6 41 47 10.2174/1874471011306010007 23470032

53. Azad GK Cook GJ Multi-technique imaging of bone metastases: spotlight on PET-CT Clin Radiol 2016 71 620 631 10.1016/j.crad.2016.01.026 26997430

54. Cook GJR PET and PET/CT imaging of skeletal metastases Cancer Imaging 2010 10 1 8 10.1102/1470-7330.2010.0022 20663736 PMC2922743

55. Torigian DA Huang SS Houseni M Alavi A Functional imaging of cancer with emphasis on molecular techniques CA Cancer J Clin 2007 57 206 224 10.3322/canjclin.57.4.206 17626118

56. Wondergem M van der Zant FM van der Ploeg T Knol RJ 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 34 935 945 10.1097/MNM.0b013e328364918a 23903557

57. Beheshti M Vali R Waldenberger P Fitz F Nader M Hammer J Loidl W Pirich C Fogelman I Langsteger W The use of F-18 choline PET in the assessment of bone metastases in prostate cancer: correlation with morphological changes on CT Mol Imaging Biol 2010 12 98 107 10.1007/s11307-009-0239-7 19588206

58. Garzon JRG de Arcocha TM Delgado-Bolton R Ceci F Ruiz SA Rincon JO Aroztegui APC Velloso MJG Vicente AMG (68)Ga-PSMA PET/CT in prostate cancer Rev Esp Med Nucl Imagen Mol 2018 37 130 138 10.1016/j.remn.2017.07.004 28941866

59. Hofman MS Lawrentschuk N Francis RJ Tang C Vela I Thomas P Rutherford N Martin JM Frydenberg M Shakher R Wong LM Taubman K Ting Lee S Hsiao E Roach P Nottage M Kirkwood I Hayne D Link E Marusic P Matera A Herschtal A Iravani A Hicks RJ Williams S Murphy DG 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 1208 1216 10.1016/s0140-6736(20)30314-7 32209449

60. Cerci JJ Fanti S Lobato EE Kunikowska J Alonso O Medina S Novruzov F Lengana T Granados C Kumar R Rangarajan V Al-Ibraheem A Hourani M Ali NS Ahmad A Keidar Z Kucuk O Elboga U Bogoni M Paez D Diagnostic performance and clinical impact of (68)Ga-PSMA-11 imaging in early relapsed prostate cancer after radical therapy: a prospective multicenter study (IAEA-PSMA study) J Nucl Med 2021 10.2967/jnumed.120.261886 34215674 PMC8805782

61. Pyka T Okamoto S Dahlbender M Tauber R Retz M Heck M Tamaki N Schwaiger M Maurer T Eiber M Comparison of bone scintigraphy and (68)Ga-PSMA PET for skeletal staging in prostate cancer Eur J Nucl Med Mol Imaging 2016 43 2114 2121 10.1007/s00259-016-3435-0 27290607

62. Costelloe CM Rohren EM Madewell JE Hamaoka T Theriault RL Yu TK Lewis VO Ma J Stafford RJ Tari AM Hortobagyi GN Ueno NT Imaging bone metastases in breast cancer: techniques and recommendations for diagnosis Lancet Oncol 2009 10 606 614 10.1016/S1470-2045(09)70088-9 19482249

63. Yu HHM Tsai YY Hoffe SE Overview of diagnosis and management of metastatic disease to bone Cancer Control J Moffitt Cancer Cent 2012 19 84 91 10.1177/107327481201900202 22487970

64. Shibata H Kato S Sekine I Abe K Araki N Iguchi H Izumi T Inaba Y Osaka I Kato S Kawai A Kinuya S Kodaira M Kobayashi E Kobayashi T Sato J Shinohara N Takahashi S Takamatsu Y Takayama K Takayama K Tateishi U Nagakura H Hosaka M Morioka H Moriya T Yuasa T Yurikusa T Yomiya K Yoshida M Diagnosis and treatment of bone metastasis: comprehensive guideline of the Japanese Society of Medical Oncology, Japanese Orthopedic Association, Japanese Urological Association, and Japanese Society for Radiation Oncology ESMO Open 2016 1 e000037 10.1136/esmoopen-2016-000037 27843593 PMC5070259

65. Garcia-Saenz JA Bermejo B Estevez LG Palomo AG Gonzalez-Farre X Margeli M Pernas S Servitja S Rodriguez CA Ciruelos E SEOM clinical guidelines in early-stage breast cancer 2015 Clin Transl Oncol 2015 17 939 945 10.1007/s12094-015-1427-3 26497356 PMC4689767

66. Gavila J Lopez-Tarruella S Saura C Munoz M Oliveira M De la Cruz-Merino L Morales S Alvarez I Virizuela JA Martin M SEOM clinical guidelines in metastatic breast cancer 2015 Clin Transl Oncol 2015 17 946 955 10.1007/s12094-015-1476-7 26683474 PMC4689775

67. Cardoso F Kyriakides S Ohno S Penault-Llorca F Poortmans P Rubio IT Zackrisson S Senkus E Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up Ann Oncol 2019 30 1674 10.1093/annonc/mdz189 31236598

68. Cardoso F Senkus E Costa A Papadopoulos E Aapro M Andre F Harbeck N Aguilar Lopez B Barrios CH Bergh J Biganzoli L Boers-Doets CB Cardoso MJ Carey LA Cortes J Curigliano G Dieras V El Saghir NS Eniu A Fallowfield L Francis PA Gelmon K Johnston SRD Kaufman B Koppikar S Krop IE Mayer M Nakigudde G Offersen BV Ohno S Pagani O Paluch-Shimon S Penault-Llorca F Prat A Rugo HS Sledge GW Spence D Thomssen C Vorobiof DA Xu B Norton L Winer EP 4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)dagger Ann Oncol 2018 29 1634 1657 10.1093/annonc/mdy192 30032243 PMC7360146

69. Rajarubendra N Bolton D Lawrentschuk N Diagnosis of bone metastases in urological malignancies—an update Urology 2010 76 782 790 10.1016/j.urology.2009.12.050 20346492

70. Ulaner GA Eaton A Morris PG Lilienstein J Jhaveri K Patil S Fazio M Larson S Hudis CA Jochelson MS Prognostic value of quantitative fluorodeoxyglucose measurements in newly diagnosed metastatic breast cancer Cancer Med 2013 2 725 733 10.1002/cam4.119 24403238 PMC3892804

71. Chacon Lopez-Muniz JI de la Cruz ML Gavila Gregori J Martinez Duenas E Oliveira M Segui Palmer MA Alvarez Lopez I Antolin Novoa S Bellet Ezquerra M Lopez-Tarruella CS SEOM clinical guidelines in advanced and recurrent breast cancer (2018) Clin Transl Oncol 2019 21 31 45 10.1007/s12094-018-02010-w 30617924 PMC6339670

72. Cardoso F Paluch-Shimon S Senkus E Curigliano G Aapro MS André F Barrios CH Bergh J Bhattacharyya GS Biganzoli L Boyle F Cardoso MJ Carey LA Cortés J El Saghir NS Elzayat M Eniu A Fallowfield L Francis PA Gelmon K Gligorov J Haidinger R Harbeck N Hu X Kaufman B Kaur R Kiely BE Kim SB Lin NU Mertz SA Neciosup S Offersen BV Ohno S Pagani O Prat A Penault-Llorca F Rugo HS Sledge GW Thomssen C Vorobiof DA Wiseman T Xu B Norton L Costa A Winer EP 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) Ann Oncol 2020 31 1623 1649 10.1016/j.annonc.2020.09.010 32979513 PMC7510449

73. Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L Kaplan R Lacombe D Verweij J New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 10.1016/j.ejca.2008.10.026 19097774

74. Hamaoka T Costelloe CM Madewell JE Liu P Berry DA Islam R Theriault RL Hortobagyi GN Ueno NT Tumour response interpretation with new tumour response criteria vs the World Health Organisation criteria in patients with bone-only metastatic breast cancer Br J Cancer 2010 102 651 657 10.1038/sj.bjc.6605546 20104228 PMC2837571

75. Katayama T Kubota K Machida Y Toriihara A Shibuya H Evaluation of sequential FDG-PET/CT for monitoring bone metastasis of breast cancer during therapy: correlation between morphological and metabolic changes with tumor markers Ann Nucl Med 2012 26 426 435 10.1007/s12149-012-0595-2 22477261

76. Dong Y Zheng S Machida H Wang B Liu A Liu Y Zhang X Differential diagnosis of osteoblastic metastases from bone islands in patients with lung cancer by single-source dual-energy CT: advantages of spectral CT imaging Eur J Radiol 2015 84 901 907 10.1016/j.ejrad.2015.01.007 25661696

77. Horger M Thaiss WM Wiesinger B Ditt H Fritz J Nikolaou K Kloth C Longitudinal computed tomography monitoring of pelvic bones in patients with breast cancer using automated bone subtraction software Investig Radiol 2017 52 288 294 10.1097/rli.0000000000000343 28002240

78. Lecouvet FE Larbi A Pasoglou V Omoumi P Tombal B Michoux N Malghem J Lhommel R Vande Berg BC MRI for response assessment in metastatic bone disease Eur Radiol 2013 23 1986 1997 10.1007/s00330-013-2792-3 23455764

79. Winfield JM Tunariu N Rata M Miyazaki K Jerome NP Germuska M Blackledge MD Collins DJ de Bono JS Yap TA deSouza NM Doran SJ Koh DM Leach MO Messiou C Orton MR Extracranial soft-tissue tumors: repeatability of apparent diffusion coefficient estimates from diffusion-weighted MR imaging Radiology 2017 284 88 99 10.1148/radiol.2017161965 28301311 PMC6063352

80. Lin NU Thomssen C Cardoso F Cameron D Cufer T Fallowfield L Francis PA Kyriakides S Pagani O Senkus E Costa A Winer EP International guidelines for management of metastatic breast cancer (MBC) from the European School of Oncology (ESO)-MBC Task Force: surveillance, staging, and evaluation of patients with early-stage and metastatic breast cancer Breast 2013 22 203 210 10.1016/j.breast.2013.03.006 23601761

81. Brown AL Middleton G MacVicar AD Husband JE T1-weighted magnetic resonance imaging in breast cancer vertebral metastases: changes on treatment and correlation with response to therapy Clin Radiol 1998 53 493 501 10.1016/s0009-9260(98)80168-2 9714388

82. Kosmin M Makris A Joshi PV Ah-See ML Woolf D Padhani AR The addition of whole-body magnetic resonance imaging to body computerised tomography alters treatment decisions in patients with metastatic breast cancer Eur J Cancer 2017 77 109 116 10.1016/j.ejca.2017.03.001 28390297

83. Kosmin M Padhani AR Gogbashian A Woolf D Ah-See ML Ostler P Sutherland S Miles D Noble J Koh DM Marshall A Dunn J Makris A Comparison of whole-body MRI, CT, and bone scintigraphy for response evaluation of cancer therapeutics in metastatic breast cancer to bone Radiology 2020 297 622 629 10.1148/radiol.2020192683 33078998

84. National Institute for Health and Clinical Excellence (NICE). Advanced breast cancer: diagnosis and treatment Clinical guideline. 2009. https://www.nice.org.uk/guidance/cg81/resources/advanced-breast-cancer-diagnosis-and-treatment-pdf-975683850181 . Accessed 16 Aug 2017.

85. Donohoe KJ Cohen EJ Giammarile F Grady E Greenspan BS Henkin RE Millstine J Smith GT Srinivas S Kauffman J Ahuja S Appropriate use criteria for bone scintigraphy in prostate and breast cancer: summary and excerpts J Nucl Med 2017 58 14N 17N 28373397

86. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology (NCCN Guidelines). Breast cancer version 1. 2018. http://www.NCCN.org .

87. Chavdarova L Piperkova E Tsonevska A Timcheva K Dimitrova M Bone scintigraphy in the monitoring of treatment effect of bisphosphonates in bone metastatic breast cancer J BUON 2006 11 499 504 17309184

88. Al-Muqbel KM Yaghan RJ Effectiveness of 18F-FDG-PET/CT vs bone scintigraphy in treatment response assessment of bone metastases in breast cancer Medicine 2016 95 e3753 10.1097/MD.0000000000003753 27227942 PMC4902366

89. Wong KK Piert M Dynamic bone imaging with 99mTc-labeled diphosphonates and 18F-NaF: mechanisms and applications J Nucl Med 2013 54 590 599 10.2967/jnumed.112.114298 23482667

90. Hamaoka T Madewell JE Podoloff DA Hortobagyi GN Ueno NT Bone imaging in metastatic breast cancer J Clin Oncol 2004 22 2942 2953 10.1200/JCO.2004.08.181 15254062

91. Araz M Aras G Kucuk ON The role of 18F-NaF PET/CT in metastatic bone disease J Bone Oncol 2015 4 92 97 10.1016/j.jbo.2015.08.002 26587375 PMC4648995

92. Vicente AMG Castrejón AS Amo-Salas M Fidalgo JFL Sanchez MMM Cabellos RA Aunion RE Madero VM Glycolytic activity in breast cancer using 18F-FDG PET/CT as prognostic predictor: a molecular phenotype approach Rev Esp Med Nucl Imagen Mol 2016 35 152 158 10.1016/j.remn.2015.08.001 26522003

93. Caresia Aroztegui AP García Vicente AM Alvarez Ruiz S Delgado Bolton RC Orcajo Rincon J Garcia Garzon JR de Arcocha TM Garcia-Velloso MJ 18F-FDG PET/CT in breast cancer: evidence-based recommendations in initial staging Tumor Biol 2017 39 1010428317728285 10.1177/1010428317728285 29025377

94. Costelloe CM Chuang HH Madewell JE Ueno NT Cancer response criteria and bone metastases: RECIST 1.1, MDA and PERCIST J Cancer 2010 1 80 92 10.7150/jca.1.80 20842228 PMC2938069

95. Avril S Muzic RF Jr Plecha D Traughber BJ Vinayak S Avril N 18 F-FDG PET/CT for monitoring of treatment response in breast cancer J Nucl Med 2016 57 Suppl 1 34S 39S 10.2967/jnumed.115.157875 26834099 PMC5228521

96. Mortimer JE Dehdashti F Siegel BA Trinkaus K Katzenellenbogen JA Welch MJ Metabolic flare: indicator of hormone responsiveness in advanced breast cancer J Clin Oncol 2001 19 2797 2803 10.1200/JCO.2001.19.11.2797 11387350

97. Kim JH Comparison of the EORTC criteria and PERCIST in solid tumors: a pooled analysis and review Oncotarget 2016 7 58105 58110 10.18632/oncotarget.11171 27517621 PMC5295415

98. Young H Baum R Cremerius U Herholz K Hoekstra O Lammertsma AA Pruim J Price P Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group Eur J Cancer 1999 35 1773 1782 10.1016/s0959-8049(99)00229-4 10673991

99. Wahl RL Jacene H Kasamon Y Lodge MA From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors J Nucl Med 2009 50 Suppl 1 122S S150 10.2967/jnumed.108.057307 19403881 PMC2755245

100. Keyaerts M Xavier C Heemskerk J Devoogdt N Everaert H Ackaert C Vanhoeij M Duhoux FP Gevaert T Simon P Schallier D Fontaine C Vaneycken I Vanhove C De Greve J Lamote J Caveliers V Lahoutte T Phase I study of 68Ga-HER2-nanobody for PET/CT assessment of HER2 expression in breast carcinoma J Nucl Med 2016 57 27 33 10.2967/jnumed.115.162024 26449837

101. Massicano AVF Marquez-Nostra BV Lapi SE Targeting HER2 in nuclear medicine for imaging and therapy Mol Imaging 2018 17 1536012117745386 10.1177/1536012117745386 29357745 PMC5784567

102. Rigaud J Tiguert R Le Normand L Karam G Glemain P Buzelin JM Bouchot O Prognostic value of bone scan in patients with metastatic prostate cancer treated initially with androgen deprivation therapy J Urol 2002 168 1423 1426 10.1097/01.ju.0000030900.55714.76 12352409

103. Teo MY Rathkopf DE Kantoff P Treatment of advanced prostate cancer Annu Rev Med 2019 70 479 499 10.1146/annurev-med-051517-011947 30691365 PMC6441973

104. Spratt DE Zumsteg ZS Feng FY Tomlins SA Translational and clinical implications of the genetic landscape of prostate cancer Nat Rev Clin Oncol 2016 13 597 610 10.1038/nrclinonc.2016.76 27245282 PMC5030163

105. Lecouvet FE Oprea-Lager DE Liu Y Ost P Bidaut L Collette L Deroose CM Goffin K Herrmann K Hoekstra OS Kramer G Lievens Y Lopci E Pasquier D Petersen LJ Talbot JN Zacho H Tombal B deSouza NM Use of modern imaging methods to facilitate trials of metastasis-directed therapy for oligometastatic disease in prostate cancer: a consensus recommendation from the EORTC Imaging Group Lancet Oncol 2018 19 e534 e545 10.1016/S1470-2045(18)30571-0 30303127

106. Padhani AR Lecouvet FE Tunariu N Koh DM De Keyzer F Collins DJ Sala E Schlemmer HP Petralia G Vargas HA Fanti S Tombal HB de Bono J METastasis reporting and data system for prostate cancer: practical guidelines for acquisition, interpretation, and reporting of whole-body magnetic resonance imaging-based evaluations of multiorgan involvement in advanced prostate cancer Eur Urol 2017 71 81 92 10.1016/j.eururo.2016.05.033 27317091 PMC5176005

107. Yoshida S Takahara T Ishii C Arita Y Waseda Y Kijima T Yokoyama M Ishioka J Matsuoka Y Saito K Fujii Y METastasis reporting and data system for prostate cancer as a prognostic imaging marker in castration-resistant prostate cancer Clin Genitourin Cancer 2020 18 e391 e396 10.1016/j.clgc.2019.12.010 31902713

108. Perez-Lopez R Mateo J Mossop H Blackledge MD Collins DJ Rata M Morgan VA Macdonald A Sandhu S Lorente D Rescigno P Zafeiriou Z Bianchini D Porta N Hall E Leach MO de Bono JS Koh DM Tunariu N Diffusion-weighted imaging as a treatment response biomarker for evaluating bone metastases in prostate cancer: a pilot study Radiology 2017 283 168 177 10.1148/radiol.2016160646 27875103 PMC6140995

109. Scher HI Morris MJ Stadler WM Higano C Basch E Fizazi K Antonarakis ES Beer TM Carducci MA Chi KN Corn PG de Bono JS Dreicer R George DJ Heath EI Hussain M Kelly WK Liu G Logothetis C Nanus D Stein MN Rathkopf DE Slovin SF Ryan CJ Sartor O Small EJ Smith MR Sternberg CN Taplin ME Wilding G Nelson PS Schwartz LH Halabi S Kantoff PW Armstrong AJ Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3 J Clin Oncol 2016 34 1402 1418 10.1200/JCO.2015.64.2702 26903579 PMC4872347

110. Jadvar H Is there use for FDG-PET in prostate cancer? Semin Nucl Med 2016 46 502 506 10.1053/j.semnuclmed.2016.07.004 27825430 PMC5119923

111. Evangelista L Zattoni F Guttilla A Saladini G Colletti PM Rubello D Choline PET or PET/CT and biochemical relapse of prostate cancer: a systematic review and meta-analysis Clin Nucl Med 2013 38 305 314 10.1097/RLU.0b013e3182867f3c 23486334

112. Schmidkonz C Cordes M Goetz TI Prante O Kuwert T Ritt P Uder M Wullich B Goebell P Bäuerle T 68Ga-PSMA-11 PET/CT derived quantitative volumetric tumor parameters for classification and evaluation of therapeutic response of bone metastases in prostate cancer patients Ann Nucl Med 2019 33 766 775 10.1007/s12149-019-01387-0 31338731

113. Filograna L Lenkowicz J Cellini F Dinapoli N Manfrida S Magarelli N Leone A Colosimo C Valentini V Identification of the most significant magnetic resonance imaging (MRI) radiomic features in oncological patients with vertebral bone marrow metastatic disease: a feasibility study Radiol Med 2019 124 50 57 10.1007/s11547-018-0935-y 30191445

114. Wang Y Yu B Zhong F Guo Q Li K Hou Y Lin N MRI-based texture analysis of the primary tumor for pre-treatment prediction of bone metastases in prostate cancer Magn Reson Imaging 2019 60 76 84 10.1016/j.mri.2019.03.007 30917943

115. Riola-Parada C García-Cañamaque L Pérez-Dueñas V Garcerant-Tafur M Carreras-Delgado JL PET/RM simultánea vs. PET/TC en oncología. Una revisión sistemática Rev Esp Med Nucl Imagen Mol 2016 35 306 12 10.1016/j.remn.2016.06.001 27424217

116. Catalano OA Nicolai E Rosen BR Luongo A Catalano M Iannace C Guimaraes A Vangel MG Mahmood U Soricelli A Salvatore M Comparison of CE-FDG-PET/CT with CE-FDG-PET/MR in the evaluation of osseous metastases in breast cancer patients Br J Cancer 2015 112 1452 1460 10.1038/bjc.2015.112 25871331 PMC4453670

117. Botsikas D Bagetakos I Picarra M Da Afonso Barisits Barisits AC Boudabbous S Montet X Lam GT Mainta I Kalovidouri A Becker M What is the diagnostic performance of 18-FDG-PET/MR compared to PET/CT for the N- and M- staging of breast cancer? Eur Radiol 2019 29 1787 98 10.1007/s00330-018-5720-8 30267154

118. Kirchner J Martin O Umutlu L Herrmann K Bittner AK Hoffmann O Mohrmann S Gauler T Theurer S Antke C Esposito I Kinner S Schaarschmidt BM Kowall B Lütke-Brintrup D Stang A Becker AS Antoch G Buchbender C Impact of (18)F-FDG PET/MR on therapeutic management in high risk primary breast cancer patients—a prospective evaluation of staging algorithms Eur J Radiol 2020 128 108975 10.1016/j.ejrad.2020.108975 32371185 PMC9587896

119. Wetter A Lipponer C Nensa F Heusch P Rübben H Schlosser TW Pöppel TD Lauenstein TC Nagarajah J Quantitative evaluation of bone metastases from prostate cancer with simultaneous [18F] choline PET/MRI: combined SUV and ADC analysis Ann Nucl Med 2014 28 405 410 10.1007/s12149-014-0825-x 24595461

120. Sonni I Minamimoto R Baratto L Gambhir SS Loening AM Vasanawala SS Iagaru A Simultaneous PET/MRI in the evaluation of breast and prostate cancer using combined Na[(18)F] F and [(18)F]FDG: a focus on skeletal lesions Mol Imaging Biol 2020 22 397 406 10.1007/s11307-019-01392-9 31236756

121. Kranzbühler B Nagel H Becker AS Müller J Huellner M Stolzmann P Muehlematter U Guckenberger M Kaufmann PA Eberli D Burger IA Clinical performance of 68Ga-PSMA-11 PET/MRI for the detection of recurrent prostate cancer following radical prostatectomy Eur J Nucl Med Mol Imaging 2018 45 20 30 10.1007/s00259-017-3850-x 29032394

122. Domachevsky L Bernstine H Goldberg N Nidam M Catalano OA Groshar D Comparison between pelvic PSMA-PET/MR and whole-body PSMA-PET/CT for the initial evaluation of prostate cancer: a proof of concept study Eur Radiol 2020 30 328 336 10.1007/s00330-019-06353-y 31332559