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68
Ga-P15-041, A Novel Bone
Imaging Agent for Diagnosis
of Bone Metastases
Rui Guo
1
, Xiangxi Meng
1
, Fei Wang
1
, Jiangyuan Yu
1
, Qing Xie
1
, Wei Zhao
1
, Lin Zhu
2
,
Hank F. Kung
3
, Zhi Yang
1
*and Nan Li
1
*
1
Key Laboratory of Carcinogenesis and Translational Research, (Ministry of Education, Beijing), NMPA Key Laboratory for
Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear
Medicine, Peking University Cancer Hospital & Institute, Beijing, China,
2
Key Laboratory of Radiopharmaceuticals, Ministry of
Education, College of Chemistry, Beijing Normal University, Beijing, China,
3
Department of Radiology, University of
Pennsylvania, Philadelphia, PA, United States
Objectives:
68
Ga-P15-041 (
68
Ga-HBED-CC-BP) is a novel bone-seeking PET
radiotracer, which can be readily prepared by using a simple kit formulation and an in-
house
68
Ga/
68
Ge generator. The aim of this study is to assess the potential human
application of
68
Ga-P15-041 for clinical PET/CT imaging and to compare its efficacy to
detect bone metastases of different cancers with
99
mTc-MDP whole-body bone
scintigraphy (WBBS).
Methods: Initial kinetic study using Patlak analysis and parametric maps were performed
in five histopathologically proven cancer patients (three males, two females) using
68
Ga-
P15-041 PET/CT scan only. Another group of 51 histopathologically proven cancer
patients (22 males, 29 females) underwent both
99
mTc-MDP WBBS and
68
Ga-P15-041
PET/CT scans within a week, sequentially. Using either pathology examination or follow-
up CT or MRI scans as the gold standard, the diagnostic efficacy and receiver operating
characteristic curve (ROC) of the two methods in identifying bone metastases were
compared (p <0.05, statistically significant).
Results: Fifty-one patients were imaged, and 174 bone metastatic sites were identified.
68
Ga-P15-041 PET/CT and
99
mTc-MDP WBBS detected 162 and 81 metastases,
respectively. Sensitivity, specificity, positive predictive value, negative predictive value
and accuracy of
68
Ga-P15-041 PET/CT and
99
mTc-MDP WBBS were 93.1% vs 81.8%,
89.8% vs 90.7%, 77.5% vs 69.2%, 97.2% vs 93.4% and 90.7% vs 88.4%, respectively.
Our results showed that the mean of SUVmax was significantly higher in metastases than
that in benign lesions, 15.1 ± 6.9 vs. 5.6 ± 1.3 (P <0.001). Using SUVmax = 7.6 as the cut-
off value by PET/CT, it was possible to predict the occurrence of metastases (AUC =
0.976; P <0.001; 95% CI: 0.946–0.999). However, it was impossible to distinguish
osteoblastic bone metastases from osteolytic bone lesions. Parametric maps based on
Patlak analysis provided excellent images and highly valuable quantitative information.
Conclusions:
68
Ga-P15-041 PET/CT, offering a rapid bone scan and high contrast
images in minutes, is superior to the current method of choice in detecting bone
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668511
Edited by:
Haibin Shi,
Soochow University, China
Reviewed by:
Min Yang,
Jiangsu Institute of Nuclear Medicine,
China
Dengfeng Cheng,
Fudan University, China
*Correspondence:
Nan Li
rainbow6283@sina.com
Zhi Yang
pekyz@163.com
Specialty section:
This article was submitted to
Cancer Imaging and
Image-directed Interventions,
a section of the journal
Frontiers in Oncology
Received: 30 August 2021
Accepted: 27 October 2021
Published: 25 November 2021
Citation:
Guo R, Meng X, Wang F,
Yu J, Xie Q, Zhao W, Zhu L,
Kung HF, Yang Z and Li N
(2021)
68
Ga-P15-041, A
Novel Bone Imaging Agent for
Diagnosis of Bone Metastases.
Front. Oncol. 11:766851.
doi: 10.3389/fonc.2021.766851
ORIGINAL RESEARCH
published: 25 November 2021
doi: 10.3389/fonc.2021.766851
metastases. It is reasonable to suggest that
68
Ga-P15-041 PET/CT could become a
valuable routine nuclear medicine procedure in providing excellent images for detecting
bone metastases in cancer patients.
68
Ga-P15-041 could become a valuable addition
expanding the collection of
68
Ga-based routine nuclear medicine procedures where
18
Ffluoride is not currently available.
Keywords: PET/CT, bisphosphonate, cancer, bone metastases, SUV and Gallium-68
1 INTRODUCTION
The bone is the third most common site of metastasis for a wide
range of solid tumors, and about 70 and 80% of cancer patients
will eventually develop bone metastasis (1–3). Bone metastasis
often predicts manifestation of cancer, which lead to poor quality
of life and shorter life span. Skeletal related events (SRE) such as
bone pain, pathological fracture and hypercalcemia are common
complications of bone metastasis, which seriously affect the
quality of life of patients (4–6). The purpose of bone imaging
was to identify bone involvement as early as possible to prevent
complications including fractures and spinal cord compression,
monitor treatment responses, and guide histological biopsies.
Methylene diphosphonate labeled with technetium-99m
(
99m
Tc-MDP) contains the smallest bisphosphonate chelator,
and is one of the most commonly used radiopharmaceutical
imaging agents over the past forty years. Due to its advantage of
overall high sensitivity and easy evaluation of the entire skeleton
at a relatively low cost in comparison to conventional
radiographs,
99m
Tc-MDP whole body bone scan (WBBS) has
become the most common method for screening bone
metastasis. But there are several disadvantages associated with
this technique, such as low specificity, hard to distinguish
between osteogenic and osteolytic lesions, and not showing the
degree of bone destruction (7–9). In addition, there have been
few improvements in radiopharmaceuticals for WBBS in the past
few decades, and the supply of
99m
Tc has become less predictable
in recent years due to the decline in the number of active nuclear
reactors for medical isotope production. However, with the rapid
development of positron emission tomography/computed
tomography (PET/CT), the role of positron tracer in the
detection of bone lesions has attracted more attention as a
potential alternative method. When WBBS fails to provide
sufficient information for diagnosis, PET/CT may become the
game-changing clinical tool to address this problem. Compared
with WBBS, PET/CT provides higher resolution bone images,
thus it could detect lesions not readily detectable by WBBS. This
method might be more suitable for the detection of bone
metastases (10–14), and it might have important clinical
significance for guiding the selection of tumor treatment and
prognosis on patient management. The combined information
provided by PET/CT fusion scans not only has advantages in
identifying malignant and benign lesions, but also reduces the
need for additional imaging procedures, thus avoiding possible
diagnostic delays. With the improvement of PET/CT equipment
resulting in higher spatial resolution, image quality,
multidimensional information and anatomical localization
have led to better images for diagnosis and improvement of
patient management.
68
Ga-P15-041 is a novel bone-seeking radiotracer, which
provides bone PET/CT imaging agents without the need for a
near-by cyclotron (15,16). The imaging agent is a combination
of a gallium-68-chelating bifunctional agent, N,N’-bis(2-
hydroxybenzyl)ethylenediamine-N,N’-diacetic acid (HBED),
and a bone-targeting group—bisphosphonate (BP). Thus,
68
Ga-P15-041 not only ensures a high specificity through the
excellent bisphosphonate binding of active bone surfaces, but
also affords a quick and facile radionuclide, gallium-68, complex
formation for the diagnosis of bone lesions. Previous report by
Zha et al. (15) has demonstrated that biodistribution and
microPET imaging studies of
68
Ga-P15-041 in normal mice
and rats showed excellent in vivo stability, high bone uptake
and retention comparable to that of
18
F-NaF. Recently,
68
Ga-
P15-041 PET/CT imaging studies in humans was reported by
Doot et al. (16). Results showed a higher contrast with more
detectable lesions than the planar bone imaging with
99m
Tc-
MDP which demonstrated the potential as a new type of positron
tracer for bone imaging. In this study we further evaluate the
ability of using maximum standardized uptake value (SUVmax)
for measuring the sensitivity, specificity, positive and negative
predictive value (PPV and NPV), and accuracy of
68
Ga-P15-041
PET/CT images to detect bone metastases in cancer patients.
2 MATERIALS AND METHODS
2.1 Production of 68Ga-P15-041
(
68
Ga-HBED-CC-BP)
P15-041 was obtained as a lyophilized kit (provided by Professor
Lin Zhu from Beijing Normal University). Radiosynthesis,
quality control, and final human dose release criteria were
performed according to previously reported procedures (15–17).
2.2 Subjects
The clinical protocol was reviewed and approved by the Ethics
Committee of Peking University Cancer Hospital (ID.
2018KT50) and it was conducted according to the latest
guidelines of the Declaration of Helsinki. All patients provided
a written informed consent before study participation. The
inclusion criteria included the following: older than 18 years;
with the ability to provide informed written consent; and with
pathological diagnosis of malignant tumor. The exclusion criteria
included any of the following: liver and/or renal dysfunction,
Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668512
pregnancy or current lactation, and inability to assume a supine
position continuously on the scanner bed. Finally, 56 patients
were enrolled, five patients (three males, two females, age 40–67 y,
average age 54 y) underwent
68
Ga-P15-041 dynamic PET/CT
imaging, and 51 patients (22 males, 29 females, age 27–84 y,
average age 56 y) underwent both
68
Ga-P15-041 PET/CT imaging
and
99m
Tc-MDP WBBS, sequentially within a week.
2.3 Bone Scintigraphy Protocol
No specific preparation was required for patients. The
intravenously administered dose of
99m
Tc-MDP was 740 to
925 MBq. The patients were instructed to empty the bladder
3 h after receiving
99m
Tc-MDP and planar images were obtained.
Planar images were acquired on a dual-head gamma camera
(Siemens, Erlangen, Germany) fitted with a low-energy high-
resolution parallel hole collimator, at the acquisition speed of 15
cm/min, with a 20% energy window centered at 140 keV. Data
acquired were stored in a 256 × 1,024 matrix.
2.4
68
Ga-P15-041 PET/CT Protocol
Similarly, no specific preparation was required for patients. An
intravenously administered dose of
68
Ga-P15-041 (157–267
MBq) was used. The specific activity of
68
Ga-P15-041 of each
patient was shown in Supplementary Table 1. PET/CT scans
were conducted by a Siemens Biograph mCT Flow 64 scanner
(Siemens, Erlangen, Germany).
Dynamic PET/CT imaging procedures were performed by the
following protocol: A low-dose CT scan (120 kV, 35 mA, slice 3
mm) was first performed, and dynamic PET acquisitions started
upon the injection of the tracer. An optimized dynamic whole-
body acquisition enabled by FlowMotion was conducted over a
duration of approximately 60 min (collection speed from fast to
slow, 10 passes). Subsequently, a whole-body PET/CT scan was
performed in 120 min after the injection, and the acquisition
speed was 1.0 mm/s to cover the whole body (slice 3 mm, filter:
Gaussian, FWHM: 5 mm), which lasted approximately 15 min.
Static PET/CT imaging was performed in 60 min after
68
Ga-P15-
041 injection. The scans covered the length from the top of the
skull to the feet, and the acquisition parameters were the same as
the 120 min acquisition of dynamic imaging.
Both dynamic and static PET images were reconstructed using a
three-dimensional iterative reconstruction with the time-of-flight
algorithm, and the low-dose CT scans were acquired in CARE Dose
4D mode (120 kV, 3.0 mm/slice). The dynamic PET scans were
segmented and reconstructed into 10 frames.
2.5 Parametric Map
According to the time-activity map, it is reasonably assumed that
the uptake of the tracer by the lesion is non-reversible. Thus, the
dynamic process of tracer uptake could be modeled with the
Patlak analysis. In this study, the parametric map was generated
for each patient, revealing the Patlak K
i
and V
b
(3). The input
function was retrieved from the images, by manually segmenting
the ascending aorta of each patient. A code developed with
MATLAB 2020b (Mathworks, MA, USA) was used to generate
the images.
2.6 Image Analysis
A Siemens workstation (MultiModality Workplace) was used for
post processing. Two experienced nuclear medicine/radiologists
reviewed and analyzed the rests of
99m
Tc-MDP WBBS and
68
Ga-
P15-041 PET/CT independently, and any inconsistencies were
resolved by consensus.
The standard protocol for bone imaging with
99m
Tc-MDP
WBBS was performed. Abnormal increases in the uptake of
99m
Tc-MDP in WBBS associated with metastatic bone lesions
were identified, if they were not periarticular area involving the
posterior vertebral body and pedicle, or rib lesions presented as
elongated uptake (18–20).
Differential diagnosis of bone metastasis and benign lesions was
based on the uptake intensity and the tomodensitometry
characteristics of the lesions observed in the CT component of
the PET/CT. Volumes of interest (VOIs) were manually drawn for
each lesion and the SUVmax values were automatically calculated.
The axial, coronal, and sagittal PET/CT images of
68
Ga-P15-041
were qualitatively analyzed by nuclear medicine physicians. All of
diagnostic criteria have been adapted based on previously published
literatures on the diagnosis of bone metastases with
18
F-NaF PET/
CT (18,21–23). Areas with
68
Ga-P15-041 uptake higher than
normalbonewereidentified as abnormal, suggesting the presence
of bone lesions. Vertebral lesions involving the vertebral body and
the posterior pedicle or extensive involvement of the vertebral body
are considered malignant. Lesions in the ribs are classified as
malignant when they present as strips of high uptake and benign
(fractures) when they involve multiple locations of ribs vertically.
According to the corresponding morphological characteristics of
PET/CT and the anatomical location provided, when degenerative
changes, fractures or other benign bone lesions (such as bone cysts)
are found at the corresponding location on CT, the lesions are
characterized as benign lesions. If lesions associated with osteogenic
changes are identified by CT, the lesions are characterized as
metastatic. When the local bone was accompanied by abnormal
radioactivity concentration without obvious abnormal density
changesonCT,itwasconsideredasbonemetastasis.
Although histopathological confirmation is considered the
golden standard for detecting bone metastases, it was virtually
impossible to obtain the information for all lesions in this study.
Where feasible, metastatic bone invasion is confirmed by
histological examination. Alternatively, clinical follow-up and/
or CT/MRI/bone scans were used to confirm the presence of
metastasis. For each patient, the presence or absence of bone
metastases is determined by combining his/her clinical,
radiographic, and biopsy pathological results. Metastatic bone
lesions are considered positive, if any of the following criteria are
present: positive pathology; other imaging tests (MRI or CT); or
progression of skeletal lesions on subsequent imaging or nuclear
medicine studies (CT, MRI, BS or
18
F-FDG-PET) in 6 to 12
months after the initial scan. According to the characteristics of
density changes identified by CT, bone metastatic lesions were
divided into osteolytic and osteogenic lesions.
In the dynamic imaging study, all metastatic lesions were
divided into four regions: spine (including the whole vertebral
column), pelvis (including the iliac, ischial and pubic bones),
Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668513
thorax and head (including ribs, scapula and skull bones), and
the extremities. To analyze the biodistribution and variability of
68
Ga-P15-041, VOIs were manually drawn for each metastastic
lesion, as well as two benign lesions, fourth lumbar vertebral,
liver and right gluteus maximus on every pass, while avoiding
major blood vessels. The software automatically calculated
SUVmax for the VOIs and the time–activity curves were
produced accordingly.
2.7 Statistical Analysis
Thequantitativedatawerepresented as mean ± standard
deviation (SD) and the qualitative data as n (%). Analysis of
variance (ANOVA) using repeated measurements was used to
compare the variation trend of SUV values in each group of
lesions in the dynamic images. Bonferroni method was used to
correct P values for multiple comparisons. Sensitivity, specificity,
accuracy, PPV and NPV of
99m
Tc-MDP WBBS and
68
Ga-P15-
041 PET/CT were calculated. The independent Student’s t-test
was used for comparison of quantitative variables between two
different groups. For paired comparisons of quantitative
variables, the paired Student’s t-test was used. A p-value less
than 0.05 was considered statistically significant for statistical
tests performed. To assess the predictive capacity of the
quantitative variables in relation to the occurrence of bone
metastasis, the area under the curve (AUC) of the receiver
operating characteristic (ROC) was calculated, with a
confidence interval (CI) of 95%. SPSS software (version 24,
IBM, NY), and Excel software (Microsoft Corporation,
Redmond, WA) were used for the statistical analysis of the data.
3 RESULTS
3.1
68
Ga-P15-041 PET/CT Dynamic
Imaging
3.1.1 Temporal Characteristic of Tracer Distribution
The clinical information of the five patients receiving the
dynamic PET scans is summarized in Table 1. A typical case is
shown in Figure 1A.Thetime–activity curves of bone
metastases, benign bone lesions, liver, L4 vertebral and right
gluteus maximus as a function of time after radiotracer injection
are shown in Figure 1B. Rapid kinetic curves for lesion uptake
suggest that bone lesions may be detected within 1 h after in
injection. Optimal images may be obtained at early time points.
Increased uptakes were observed in the L4 vertebral right gluteus
maximus where a relatively lower liver activity was found
comparing with bone metastases. Liver and right gluteus
maximus activity gradually reduced to a stable level at later
time points, while the activity of L4 vertebral with prolonged
slow rise to stable level. The activity of bone metastases and bone
benign lesions consistently increased over time. In comparison,
the SUVmax values of spinal bone, pelvic bone and extremities
bone metastases were statistically different from those of benign
bone lesions, liver, L4 vertebral and right gluteus maximus
(P <0.05). In contrast, the SUVmax values of the thorax and
head metastases were not statistically different from those of
benign bone lesions (P = 0.893), but they were statistically
different from those of liver, muscle and normal bone (P <0.05).
3.1.2 The Parametric Map
Patlak maps of the five patients were generated, and the
representative K
i
map is shown in Figure 1C as the maximum
intensity projection. As demonstrated by the Patlak map, the K
i
parameter was specifically increased on the lesion sites (0.12 ±
0.013), indicating preferentially and non-reversibly uptake of the
tracer. The whole skeleton displayed an elevated, positive K
i
,
while the bladder and the ureter showed extremely high
parametric values.
3.2 Comparison Between
68
Ga-P15-041
PET/CT and
99
mTc-MDP WBBS
3.2.1 Patient-Based Analysis
A total of fifty-one tumor patients underwent
99m
Tc-MDP WBBS
and
68
Ga-P15-041 PET/CT examination within one week, and
their clinical information is shown in Table 2.
Of the fifty-one patients studied, 47 showed abnormal tracer
uptake on
68
Ga-P15-041 PET/CT, and 45 (45/47, 97.8%) of them
were finally diagnosed as bone metastases based on biopsy and
imaging follow-up. Among them, 12 patients displayed single
bone metastases and 43 patients exhibited multiple bone
metastases. In 42 of 45 patients, PET/CT clearly found
malignant bone invasion, and bone lesions with increased
uptake of
68
Ga-P15-041 were identified by PET scans with
corresponding changes in bone density observed by CT scans.
An example is shown in Figure 2. Although three patients
showed a higher bone uptake without changes in CT
morphology on spine and pelvis, these patients were later
confirmed by the follow-up CT showing a new high-density
lesion colocalized with the high tracer uptake. Two patients, who
were suspected of bone metastasis with lower uptake, but showed
no changes in the follow-up CT. They were reported as false
positives of
68
Ga-P15-041 PET/CT. Four patients showed no
metastases by follow-ups.
99m
Tc-MDP WBBS correctly detected
39 of 47 patients with metastases and three patients without
TABLE 1 | Information of Patients Enrolled in
68
Ga-P15-041 PET/CT Dynamic Imaging.
No. Gender Age (years) Diagnosis Weight (kg) Dose (MBq)
1 Male 67 Prostate cancer 70 193.1
2 Female 49 Lung cancer 72 208.3
3 Female 55 Lung cancer 74 220.5
4 Male 40 gastric cancer 65 185.0
5 Male 59 colon cancer 68 189.1
Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668514
metastases, and all these patients were correctly diagnosed with
68
Ga-P15-041 PET/CT. Three patients showed false-positive and
six patients showed false-negative. The final diagnosis by PET/
CT and WBBS was concordant for 44 (86.3%) patients (39 true
positive, three true negative, and two false positive) and
discordant for seven (13.7%) patients. The sensitivity,
specificity, PPV, NPV and accuracy of all the two imaging
techniques for detection of bone metastases of patients are
shown in Tables 3,4.
3.2.2 Lesion-Based Analysis
Finally, 174 bone metastases were confirmed through
histopathological and imaging follow-up on 51 patients
(Table 3).
68
Ga-P15-041 PET/CT detected 209 (162 true
positive; 47 false positive) lesions with bone metastases, and
427 benign lesions (415 true positive; 12 false positive).
99m
Tc-
MDP WBBS alternative was able to detect 117 (81 true positive;
36 false positive) bone metastases and 272 benign lesions (254
true positive; 18 false positive).
68
Ga-P15-041 PET/CT detected
93.1% (162/174) metastases, corresponding to 3.2 bone
metastases (1–24) per patient. However, it appears that
99m
Tc-
MDP WBBS was able only to detect 46.56% (81/174) of the
lesions. There was a significant statistical difference between
them (P<0.001).AnexampleisshowninFigure 3.
Sensitivity, specificity, PPV, NPV and accuracy of
68
Ga-P15-
041 PET/CT and
99m
Tc-MDP WBBS were 93.1% vs 81.8%, 89.8%
vs 90.7%, 77.5% vs 69.2%, 97.2% vs 93.4% and 90.7% vs 88.4%,
respectively (Table 4).Therewere12falsenegativelesions
mainly small osteolytic metastases, and there were 47 false-
TABLE 2 | Clinical Characteristics of Participants for Comparison Study between
68
Ga-P15-041 PET/CT and
99m
Tc-MDP WBBS.
Characteristic Value
No. of patients 51
Male-to-female ratio 1.0:1.32 (22:29)
Mean age ± SD, years (range) 56 ± 10 (27–84)
Primary tumor types No. (%)
Lung cancer 22 (43.14%)
Breast cancer 14 (27.45%)
Melanoma 4 (7.84%)
Intestinal cancer 4 (7.84%)
Prostate cancer 3 (5.88%)
Renal cancer 2 (3.92%)
Hepatocarcinoma 1 (1.96%)
Nasopharyngeal Cancer 1 (1.96%)
A
B
FIGURE 1 |(A–C) Pharmacokinetics of
68
Ga-P15-04.1(A) Dynamic Maximum-intensity projections (MIP) of patient #3 who received 220.5 MBq
68
Ga-P15-041. Top
row indicates starting time (min) of whole-body scan. (B) Kinetic curves for SUVmax of different sites and lesions with time. Rapid uptake in bone lesions suggest
that optimal images may be obtained at early time points. (C) Patlak maps and static SUV image of a representative patient (Same patient as in panel A). (C1, C2)
The MIP and a sagittal slice of the Patlak map; (C3) the merged image of the Patlak map and CT; (C4) the corresponding sagittal CT slice; (C5, C6) the
corresponding sagittal slice of the routine PET and fused PET/CT.
Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668515
positive lesions observed in several high-density foci
accompanied by increased tracer uptake.
Locations and final diagnosis of 162 lesions with increased
68
Ga-P15-041 PET/CT uptake are summarized in Table 5. Most
bone metastases were detected in the spine skeleton, while the
extremities have the least.
3.3 Analysis of
68
Ga-P15-041 Uptake of
Bone Metastases and Benign Lesions
The SUVmax of the lesions were recorded and compared
between 162 bone metastases and 415 benign bone lesions in
the
68
Ga-P15-041 PET/CT. The mean of the SUVmax values was
significantly higher in bone metastases than in benign lesions
TABLE 3 | Patient-based and Lesion-based Metastases Detection on
68
Ga-P15-041 PET/CT and
99m
Tc-MDP WBBS.
By patients
Group Patients [
68
Ga]Ga-P15-041
99m
Tc-MDP
+−+−
metastases 45 45 0 39 6
no metastases 6 2 4 3 3
By lesions
Group Lesions [
68
Ga]Ga-P15-041
99m
Tc-MDP
+−+−
metastases 174 162 12 81 18
no metastases 462 47 415 36 254
AB
FIGURE 2 |
99m
Tc-MDP WBBS and
68
Ga-P15-041 PET/CT in a colon cancer patient. (A)
99m
Tc-MDP WBBS appeared to show no abnormal uptake. (B) MIP of
68
Ga-P15-041 and the axial fused PET/CT showed moderate uptake in left 7th rib (arrow) with an osteoblastic change on the axial CT (arrow).
TABLE 4 | Comparison of Bone Metastases Detection Efficiency Between
68
Ga-P15-041 PET/CT and
99m
Tc-MDP WBBS Based by Patients and by Lesions.
Diagnostic efficiency By patients By lesions
[
68
Ga]Ga-P15-041
99m
Tc-MDP P [
68
Ga]Ga-P15-041
99m
Tc-MDP P
Sensitivity, % 100.0% 86.7% <0.05* 93.1% 81.8% <0.05*
Specificity, % 66.7% 50.0% >0.999 89.8% 90.7% =0.34
PPV, % 95.7% 92.9% =0.664 77.5% 69.2% =0.1
NPV, % 100.0% 33.3% =0.07 97.2% 93.4% <0.05*
Accuracy, % 96.1% 82.4% =0.051 90.7% 88.4% <0.05*
PPV, positive predictive value; NPV, negative predictive value. *Statistically significant.
Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668516
(15.1 ± 6.9 vs. 5.6 ± 1.3, P< 0.001) (Figure 4A). Using the
SUVmax, it was possible to predict the occurrence of bone
metastases, with the AUC of 0.976 (95%CI: 0.946–0.999), and
the sensitivity, specificity, PPV, NPV and accuracy were 95.1,
95.8, 95.1, 95.8, and 95.5%, respectively. An SUVmax above 7.6
always represented bone metastases (Figure 5).
Among 162 true positive lesions detected by
68
Ga-P15-041
PET/CT, 72 lesions (44.4%) showed characteristic osteoblastic
metastases with SUVmax of 14.2 ± 6.6; whereas 82 lesions
(50.6%) showed osteolytic with SUVmax of 13.7 ± 7.7, and
eight lesions (5%) showed no morphology changes on PET/CT.
The mean of the SUVmax values was not significantly difference
between osteoblastic bone metastases and osteolytic bone
metastases (P = 0.887), which was presented in Figure 4B. The
performances including sensitivity, specificity, PPV, NPV of
68
Ga-P15-041 PET/CT in different types of bone metastases
were listed in Table 6.
Among the 51 patients, there were 22 lung cancers, 14 breast
cancers and 15 other cancers. The SUVmax of 22 patients with
lung cancer and 14 patients with breast cancer were 15.3 ± 7.0
and 14.5 ± 7.4, respectively, showing no statistical difference
(p = 0.753). A typical case is shown in Figure 6.
4 DISCUSSION
Bone metastasis is a major cause of pain and it increases the risk
of SRE in cancer patients (4–6). Cancer patients with bone
metastases are rarely cured; therefore, accurate diagnosis of
bone metastasis is essential for patient management providing
information on initial staging, treatment planning, restaging,
monitoring, and survival prediction (24–26). At present,
99m
Tc-
MDP WBBS is the most commonly screening method for bone
metastasis, but it offers a detecting method with high sensitivity
and low specificity. Nevertheless, the limited specificity of WBBS
often requires additional examinations to confirm its accuracy,
especially in patients with only one single bone metastatic lesion.
As an alternative,
18
F-NaF PET/CT has been shown to be
superior to planar bone imaging in the diagnosis of bone
metastases. However,
18
F-NaF PET/CT is not widely available
and more expensive, especially in developing countries, and the
procedure requires a cyclotron and a team of skilled staff (16,27).
Decades after the introduction of
99m
Tc-MDP bone scan, it has
been evolved into a basic core business for nuclear medicine
department. Recent success in using
68
Ga/
68
Ge generator
generator-based
68
Ga-DOTATATE and
68
Ga-PSMA-11 for
A
BC
FIGURE 3 |
99m
Tc-MDP WBBS and
68
Ga-P15-041 MIP in a 72 y patient with Left lung adenocarcinoma. (A)
99m
Tc-MDP WBBS showed multiple high uptake in
right 8th rib, left 9th rib, left ilium, bilateral pubic, and thoracolumbar. (B) MIP of
68
Ga-P15-041 showed more high uptake lesions (black and red arrow). (C)
99m
Tc-
MDP WBBS after one year later showed disease progression, and right ilium and left femur (black arrow) showed new high uptake.
TABLE 5 | Location and Number Diagnosis of the Skeletal Lesions in
68
Ga-P15-041 PET/CT and
99m
Tc-MDP WBBS.
Body Regions
68
Ga-P15-041 PET/CT
99m
Tc-MDP WBBS P
Putative True P/T (%) Putative True P/T (%)
Spine 94 75 79.8% 56 38 67.9% 0.101
Pelvis 56 47 83.9% 27 19 70.4% 0.091
Thorax and head 46 29 63.0% 26 16 61.5% 0.899
Extremities 13 11 84.6% 8 8 100% 0.505
Total 209 162 77.5% 117 81 69.2% 0.1
Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668517
routine diagnosis of neuroendocrine and prostate cancer,
respectively, would likely to increase the acceptance of
68
Ga
tracers for routine clinical application.
68
Ga-P15-041 PET/CT,
reported in this paper could become a valuable addition
expanding the collection of
68
Ga-based routine nuclear
medicine procedures.
It is known that
68
Ga based bone targeting tracers can be
useful alternative choices because
68
Ge/
68
Ga generators are
relatively inexpensive, readily accessible and easy to operate
(28,29). Noticeably,
68
Ga-DOTA-ZOL was also reported as a
useful for evaluation of bone metastasis (30–32). Synthetic
peptides containing the arginine-glycine-aspartate (RGD)
sequence motif are active modulators of cell adhesion and can
bind specifically to integrin avb3. Mi et al. (33) reported
18
F-
Alfatide II PET/CT can be used to detect skeletal and bone
marrow metastases, with nearly 100% sensitivity in osteolytic,
mixed and bone marrow lesions. The sensitivity of
18
F-Alfatide II
PET/CT in osteoblastic metastases is relatively low but still
significantly higher than that of
18
F-FDG PET/CT. Moreover,
the mechanisms of bisphosphonate uptake to active bone
surfaces for
68
Ga-P15-041 are analogous to those of MDP,
providing a rationalized comparability of bone metastasis.
Therefore,
68
Ga-P15-041 is a novel bisphosphonate bone-
seeking PET imaging agent with relatively low effective dose
when compared with
99m
Tc-MDP and
18
F-NaF (16).
Results reported for
68
Ga-P15-041 in a large patient
population consisting of both osteoblastic and osteolytic
lesions displayed consistent higher uptakes. Adding dynamic
imaging with Patlak map was found to be highly effective in
assisting the diagnosis. Apart from static acquisition, whole-body
dynamic PET imaging better reflects the kinetic aspect of tracer
uptake, through continuous acquisition over an extended period
of time (34). Different types of parametric maps have been
developed to visualize the kinetic parameters based on the
dynamic imaging (35). Patlak plot is an important parametric
map which was found useful in
99m
Tc-MDP (36). Compared to
the static PET images from which the parametric map was
calculated, the Patlak map visualized the metastatic lesions
clearly. Due to this enhanced specificity, the Patlak map may
enhance the accuracy of diagnosis of bone diseases.
Compared to
99m
Tc-MDP, patients undergoing
68
Ga-P15-
041 PET/CT required a shorter scanning time (1 h vs. 3 h), which
may lead to better tolerability and improved patient compliance.
Due to the physics of positron emission and in vivo kinetics of
the tracer, the image quality of
68
Ga-P15-041 PET/CT is superior
to planar bone scintigraphy. Many lesions missed by the
99m
Tc-
MDP WBBS, including bone metastases and benign bone lesions
were detected by PET/CT scan. The CT component of
68
Ga-P15-
041 PET/CT can have added advantage of revealing the
anatomical morphology and density change of lesions, which is
helpful in improving the accuracy of the diagnosis of
bone metastases.
Results of
68
Ga-P15-041 PET/CT scans demonstrated a
higher sensitivity, NPV and accuracy for diagnosis of bone
metastases than WBBS (sensitivity 93.1% vs. 81.8%, NPV
97.2% vs. 93.4%, accuracy 90.7% vs.88.4%).Therewas
observable difference in sensitivity and no difference in
specificity and accuracy in the patient-based analysis, probably
because the diagnosis of bone metastases in patients required
only one lesion to be identified. However, the specificity for both
A
B
FIGURE 4 | Comparison of SUVmax between different groups in
68
Ga-P15-041 PET/CT. (A) 162 bone metastases and 415 benign lesions. (B) Approximately 72
osteoblastic bone metastases and 82 osteolytic bone metastases.
FIGURE 5 | ROC of SUVmax in
68
Ga-P15-041 PET/CT to discriminate bone
metastases from benign lesions.
Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668518
tracers showed no statistical difference, and it may be due to the
fact that the density and sizes of some osteoblastic lesions did not
change in the follow-up CT or MRI scans. Based on our research
criteria for the diagnosis, these lesions eventually were diagnosis
as false positives. These types of osteoblastic lesions were
difficult, if not impossible, to identify by CT or MRI and they
usually took longer to follow-up.
Analysis of images by SUVmax was employed as an effective
tool in the estimation of the intensity of radiopharmaceutical
uptake in the lesion, the evaluation of the disease, and
interpatient comparison (14,37). Published studies have
suggested that SUVmax can effectively differentiate the
metabolic changes of
18
F-NaF PET/CT bone lesions, which
supplemented by visual qualitative evaluation, can distinguish
benign and metastasis lesions (38,39). Our study also shows that
SUVmax was significantly higher in bone metastases than in
benign lesions (15.1 ± 6.9 vs. 5.6 ± 1.3, P<0.001). When the
SUVmax is greater than 7.6, it is likely to be recognized as bone
metastases, with the sensitivity, specificity and accuracy as high
as 95.1, 95.8, and 95.5%, respectively. There were also
overlapping SUVmax values between benign lesions and bone
metastases. Degenerative bone lesions accompanied by
inflammation and certain bone metastases with relatively low
metabolism are still difficult to diagnose, it may be rely on MRI to
improve the detection. In the future, further prospective studies
are needed to establish the role of SUVmax as a semi-
quantitative parameter in
68
Ga-P15-041 PET/CT in accurately
identifying benign lesions to skeletal metastatic diseases.
The kinetic data and SUVmax values observed in these
patients were very consistent with those previously reported by
Doot et al. (16), which confirming the reproducibility of this
tracer on detecting metastasis in cancer patients at different
TABLE 6 | Diagnostic efficiency of
68
Ga-P15-041 in different types of bone metastases.
Diagnosticefficiency osteoblastic metastases Osteolytic metastases Metastases with no morphology changes P
Sensitivity, % 100.0% 90.1% 72.7% <0.001*
Specificity, % 90.3% 87.5% 71.4% =0.357
PPV, % 63.16% 96.5% 80% <0.001*
NPV, % 100.0% 70% 62.5% <0.001*
Accuracy, % 91.65% 89.6% 72.2% =0.057
*Statistically significant.
AB
FIGURE 6 | MIP PET images of two patients with multiple bone metastases. (A) A 53 y male patient with Left lung adenocarcinoma. (B) A 50 y female patient with
invasive ductal carcinoma of the left breast.
Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 7668519
nuclear medicine departments. There are several other
68
Ga
labeled bisphosphonates which have appeared in the literature
(40–45). No direct comparison of these tracers in cancer patients
has been reported. However, based on results included in this
paper and other encouraging data presented previously, it is
reasonable to suggest that
68
Ga-P15-041 PET/CT is a candidate
worthy of further clinical evaluation.
It is well known that bone metastases were classified into
osteoblastic and osteolytic lesions (46,47). Based on the
difference of CT density they may be identified; it was found
that osteolytic lesion may have a poorer prognosis and may
require different treatments. Calculated SUVmax values based on
PET/CT may assist in detecting bone metastases without
abnormal density change on CT, which is a useful supplement
to CT qualitative assessment. However, there is no significant
difference in SUVmax between bone metastases from different
primary tumors (lung cancer vs. breast cancer) and between
osteoblastic and osteolytic lesions. It is likely that partial
osteolytic lesions may be accompanied by osteogenic changes,
which might affect the SUVmax values observed by PET/
CT scans.
Several limitations must be considered in this study. First of
all, a great majority of the patients lacked histopathological
verification of the bone metastases, resulting to the reliance of
imaging follow-up as the standard of reference. This may
increase the clinical heterogeneity of patient samples, but
further stratification by obtaining histological proof of all
skeletal lesions is either impractical or clinically unethical.
Therefore, non-invasive imaging examination results that have
not been strictly verified by histological examination are
acceptable under the current situation. Secondly, despite the
statistically significant differences there is an overlap of SUVmax
values between bone metastases and benign lesions. Although a
large number of patients were analyzed, various cancer categories
may lead to increased clinical heterogeneity, and due to limited
patient data, we were not able to perform subgroup analysis for
each cancer category.
5 CONCLUSION
Results presented in this paper suggest that
68
Ga-P15-041 in
conjunction with PET/CT imaging is suitable for noninvasive
detection of bone metastases in cancer patients. Whole body
68
Ga-P15-041 PET/CT scans are more sensitive and accurate than
those of conventional
99m
Tc-MDP WBBS in detecting bone
metastases. Compared to
99m
Tc-MDP, this imaging method has
advantages of being able to perform earlier imaging and providing
images with better contrast. Using SUVmax as the key parameter,
it can serve as a useful means for the quantification of PET/CT,
and it may also improve the differentiation between bone
metastases and benign lesions.
68
Ga-P15-041 in conjunction
with PET/CT may serve as a method of choice for diagnosis of
bone metastases in cancer patients in the future.
DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by the Medical Ethics Committee of Peking University
Cancer Hospital. The patients/participants provided their
written informed consent to participate in this study.
AUTHOR CONTRIBUTIONS
RG, ZY, and NL jointly designed the study and executed the
protocols. RG and JY took the major responsibility in the study
cohort, and XM in data analysis. WZ assisted the data
acquisition. JY and FW were involved in the image evaluation.
NL and ZY jointly supervised the whole research process,
conceptually designed the research ideas and provided
resources. LZ provided the lyophilized kit. QX was in charge of
drug synthesis. HK and NL helped draft the manuscript. All
authors provided critical feedback and helped shape the research,
analysis, and manuscript, and discussed the results. All authors
contributed to the article and approved the submitted version.
FUNDING
This work was financially supported by the National Natural
Science Foundation (No. 81871387; No. 81871386), the
Beijing Natural Science Foundation (No. 7202027), and the
Beijing Municipal Administration of Hospitals—Yangfan
Project (ZYLX201816).
SUPPLEMENTARY MATERIAL
The Supplementary Material for this article can be found online at:
https://www.frontiersin.org/articles/10.3389/fonc.2021.766851/
full#supplementary-material
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Guo et al. 68Ga-P15-041 Diagnosis of Bone Metastases
Frontiers in Oncology | www.frontiersin.org November 2021 | Volume 11 | Article 76685112
