The diagnostic performance of 18F-FDG PET/CT versus 18F-NaF PET/CT in breast cancer with bone metastases: an indirect comparative meta-analysis

doi:10.21203/rs.3.rs-2211568/v1

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The diagnostic performance of ¹⁸F-FDG PET/CT versus ¹⁸F-NaF PET/CT in breast cancer with bone metastases: an indirect comparative meta-analysis

https://doi.org/10.21203/rs.3.rs-2211568/v1

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Purpose: This study aimed to evaluate the comparison of the diagnostic performance of ¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT in breast cancer patients with bone metastases.

Materials and Methods: The databases PubMed and Embase were used to search the English literature on the diagnostic performance of¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT for breast cancer bone metastases. Two authors independently extracted data. Studies were selected for analysis if the data presented in the study reports could be used to construct a 2×2 contingency table. The methodology quality of the enrolled studies was assessed by QUADAS-2, and forest plots were generated based on the sensitivity and specificity of ¹⁸F-FDG PET/CT versus ¹⁸F-NaF PET/CT in the diagnosis of breast cancer bone metastases. Stata Software Version 14.0 (Stata Corporation, College Station, TX, USA) was used for statistical processing.

Results: A total of 14 articles were identified, eight of which were about the analysis of ¹⁸F-FDG PET/CT in the diagnosis of breast cancer bone metastases, five of which were about ¹⁸F-NaF PET/CT, and one article was an analysis of the diagnostic performance of both them. The studies of ¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT included 530 and 389 patients, respectively. The pooled sensitivities were 0.88 (95% CI: 0.80-0.99) for ¹⁸F-FDG PET/CT and0.98 (95% CI: 0.92-1.00) for ¹⁸F-NaF PET/CT, respectively, and the pooled specificities were 0.99 (95% CI: 0.98-1.00) and 0.91 (95% CI: 0.76-0.97), respectively. The area under the SROC curve ofboth¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT were 0.99 (95%CI: 0.98-1.00),, of which ¹⁸F-FDG PET/CT 1038 lesions were included and a sensitivity of 0.84 (95% CI: 0.67-1.00) and specificity of 1.00 (95% CI: 0.98-1.00) were reported for lesion-based¹⁸F-FDG PET/CT for BM. Compared with ¹⁸F-FDG PET/CT,¹⁸F-NaF PET/CT showed higher sensitivity (98% vs 88%, p= 0.09), but lower specificity (91% vs 99%, p=0.13), both of which were not statistically significant.

Conclusions: The results showed that ¹⁸F-NaF PET/CT and ¹⁸F-FDG PET/CT are accurate methods for detecting bone metastases in breast cancer patients. The diagnostic accuracy of both is the same.

Breast cancer

bone metastasis

18F-FDG PET/CT

18F-fluoride PET

meta-analysis

According to the latest global cancer data statistics, there were about 2.26 million newly diagnosed breast cancer cases in the world in 2020, accounting for nearly 25% of female cancer cases, and breast cancer is the most common cancer among women in 154 out of 185 countries [1]. The incidence of bone metastasis in breast cancer patients is about 8%, but in patients with advanced breast cancer, which can reach 30-85% [2]. At present, breast cancer is still the disease with the largest number of female cancer deaths. In 2020, 680,000 women worldwide died for breast cancer, and the main cause of death is not primary cancer, but metastatic diseases [1, 3]. Bone metastases (BM) can lead to disorders of bone metabolism and lead to bone-related events, seriously affecting the quality of life of patients, and even life-threatening [4]. One study has shown that BM is an important factor affecting the prognosis of breast cancer. The 5-year survival rate of patients with early-stage breast cancer without metastasis is as high as 90%, and once BM occurs, the 5-year survival rate will be reduced to 10% [5]. There is no cure for the patients with bone metastasis of breast cancer at present, but appropriate anti BM treatment can prolong their survival period and improve their quality of life, so it is important to accurately assess whether breast cancer patients have BM [6].

X-ray is routinely used to screen for bone disease, but it is not an accurate tool for early BM because it only detects lesions when calcium is lost by 30-50% [7]. Bone scan is an imaging technique for detecting bone lesions with high sensitivity but low specificity [8]. Therefore, more sensitive and accurate detection methods to detect BM in breast cancer are needed to ensure the detection of lesions and to implement interventions as early as possible to improve the survival time of patients. Positron emission tomography/computed tomography (PET/CT), as an advanced diagnostic imaging technology, can simultaneously provide metabolic information and accurate anatomical localization, which has broad application prospects in the diagnosis, staging, relocation and treatment evaluation of various malignant tumors [9, 10]. Fluorine-18 fluorodeoxyglucose (¹⁸F-FDG), a commonly used tracer in PET/CT has been widely used in the diagnosis, staging and follow-up of breast cancer patients due to its high diagnostic performance in detecting lesions [11]. ¹⁸F-Sodium fluoride (¹⁸F-NaF), as a bone-specific radiotracer, can observe changes in bone activity, and has been widely used in the detection of bone lesions in previous clinical studies [12, 13]. In patients with breast cancer BM, although osteolytic metastases are the predominant, osteogenic metastases also account for a relatively large proportion, about 15-20% [14-16]. It is well known that ¹⁸F-FDG is mainly sensitive to the detection of osteolytic metastases [17], so the current meta-analysis reviewed published studies about the detection of BM in breast cancer by PET/CT. The aim of the study was to quantitatively evaluate the diagnostic performance of ¹⁸F-FDG and ¹⁸F-NaF as PET/CT tracers in the detection of BM in breast cancer patients.

Literature Search to Identify Related Studies

The guidelines are conducted according to the requirements of the Cochrane Collaboration’s Systematic Review and Preferred Reporting Project Systematic Review and Meta-Analysis (PRISMA) [18]. The English literature of ¹⁸F-FDG PET/CT or ¹⁸F-NaF PET/CT for detecting BM of breast cancer was retrieved through PubMed and Embase databases. Systematic search using multiple keywords including: (“PET/CT” OR “PET-CT” OR “positron emission tomography/computed tomography” OR “positron emission tomography-computed tomography”) AND (“breast cancer” OR “breast carcinoma” OR “mammary cancer” OR “breast tumor”) AND (“bon* metastasis” OR “skeletal metastases” OR “osseous metastasis”) AND (“¹⁸F-Fluorodeoxyglucose” OR “¹⁸F-FDG” OR “¹⁸F-NaF” OR “¹⁸F-fluoride”). The publication period is limited from January 1, 2000 to January 31, 2022. The final article list was supplemented by an extensive cross-check of the reference lists of all retrieved articles.

Study Selection and Quality Assessment

Two reviewers independently screened all titles and read abstracts, the full text of selected articles was reviewed to determine eligibility for inclusion. Data extraction and evaluation were performed independently by two authors, and any disputes were resolved by consensus by a third reviewer. Studies included in this meta-analysis should meet all of the following inclusion criteria: (i) breast cancer patients of all ages, at any stage of disease, regardless of treatment status; (ii) identified using ¹⁸F-FDG PET/CT or ¹⁸F-NaF PET/CT imaging and characterizing BM in breast cancer patients; (iii) reference standards should include at least histopathological findings or CT, magnetic resonance imaging (MRI), clinical follow-up over 6 months; (iv) A 2 × 2 contingency table can be constructed by directly extracted or that allowed to calculate true positive (TP), false positive (FP), false negative (FN), and true negative (TN) values based on sensitivity, specificity, negative prediction, positive prediction etc. provided in the article. The exclusion criteria were as follows: (i) The study sample was less than 10 patients with breast cancer; (ii) The tracer of PET/CT was not ¹⁸F-FDG or ¹⁸F-NaF; (iii) Studies with multiple published data or subsets of data were excluded; (iv) Case reports, letters, editorials, reviews, animal, in vitro studies and studies that did not contain the original data were also excluded; (v) results from different imaging modalities were presented jointly, and studies that could not discriminate between test performance assessments of individual imaging modalities were also excluded.

QUADAS-2 is used as quality assessment of diagnostic accuracy, which consists of 4 key areas covering patient selection, index tests, reference standards, and flow of patients through the study, and timing of index tests and reference standards (“flow and time”) [19].

Data Extraction

Data extraction was performed independently by 2 investigators. For each relevant study, the data collected included the following: (i) basic information on each eligible study, such as first author, publication time, country, sample size; (ii) median age, patient selection (continuous or non-continuous) and the patient’s clinical background data and other characteristics; (iii) Information on study design; (iv) Exam results, including the number of TP, FP, TN, and FN results from the included studies; (v) parameters of CT techniques for ¹⁸F-FDG PET or ¹⁸F-NaF-PET/CT. Once there is dispute among reviewers, a third researcher evaluates all discordant items until consensus is reached.

Statistical Analysis

Stata software version 14.0 (Stata Company, College Station, TX, USA) was conducted for statistical analysis of the current meta-analysis. The diagnostic performance of ¹⁸F-FDG-PET and ¹⁸F-NaF-PET / CT in breast cancer BM was evaluated using specificity, sensitivity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic ratio (DOR), and summary subject working characteristic (SROC) curves to calculate the area under the curve (AUC) and 95% confidence interval (CI) based on TP, FP, FN, and TN values extracted in the enrolled studies. Hierarchical logistic regression models were used to calculate general estimates of sensitivity, specificity for enrolled studies. For each study on the forest map, the corresponding 95% CIs is used to plot the index and evaluate it in a graphical way. Heterogeneity test analysis between enrolled studies with Cochran’s Q test and Higgins I² test [20]. In Cochran’s Q test, p < 0.05 was the test criterion, indicating the existence of heterogeneity. The degree of heterogeneity was assessed using the Higgins I² test, using the following criteria: an inconsistency index I²<50% was considered likely to be unimportant for heterogeneity; I²=50-80% was considered moderate heterogeneity; I²>80% indicated significant heterogeneity. ¹⁸F-FDG PET/CT subgroup analysis was based on study sample size, mean age, type of study design, patient selection, attenuation correction, minimum scan slice thickness, etc. Funnel plot and Deeks asymmetry test for assessment of publication bias in ¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT [21]. Two-sample Z-test was used to evaluate the difference in the diagnostic performance of the two methods for BM detection of breast cancer, and p<0.05 was considered to be statistically significant.

Eligible Studies and Quality Assessment

A literature search identified 349 potentially relevant articles. After screening titles and abstracts, a total of 211 articles of review, irrelevant topics, case report, conference and other were excluded after gradually eliminating overlap. Then reading the full text, 25 articles out of 39 studies were excluded because they were not fully published in English (n = 1), it was impossible to extract enough data to construct a 2 × 2 contingency table (n = 6), and further exclusion of studies not in the area of interest (n = 18). Finally, 14 literatures on the diagnostic performance of ¹⁸F-FDG or ¹⁸F-NaF PET/CT in breast cancer BM were included for the current meta-analysis. The identification and selection process for studies is shown in Fig. 1.

A total of 14 articles [15, 22–34], consisting of 8 ¹⁸F-FDG PET/CT studies, 5 ¹⁸F-NaF PET/CT studies, and 1 study of both ¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT met the inclusion criteria and included 847 patients. The study sample size ranged from 20 to 150 patients with mean age ranging from 43.8–60 years old. All 14 articles were published between 2010 and 2019, including 8 prospective studies and 6 retrospective studies. Among the included studies, 4 included breast cancer patients who had previously received treatment, 3 were newly recruited breast cancer patients clinically suspected of having BM, and 8 included treated and newly recruited patients. The baseline characteristics of each study are presented in Table 1, and the parameters of PET/CT used in each enrolled study are presented in Table S1. The quality assessment of each study was assessed using the QUADAS-2 tool, and the result revealed that all 14 included studies met at least 5 of the 7 reference criteria (ie, 4 items in the risk of bias, patient selection, index test, reference standard, flow and timing and 3 items in application concerns, patient selection, index test, reference standard) and was therefore considered satisfactory [35]. For patient selection, 5 studies [22, 24, 25, 29, 32] were considered to be high-risk because they only used imaging and follow-up results as reference standards. Moreover, one of the studies had only a follow-up of two months [24], which was also considered high-risk. Risk of bias for flow and time of most studies were unclear because they did not report the time interval between the index and the reference standard trial. The results of the QUADAS-2 assessment are shown in Table S2.

Table 1

Clinical Characteristics and Diagnostic Results of the Detection of Bone Metastases Reported in Each Eligible Study.
First author	Country	year	No.patients	No. lessions	Study design			Clinical setting	Mean age (range)	Patient-Based Analysis				Lesion-Based Analysis
First author	Country	year	No.patients	No. lessions	prospective	Multicenter	Consecutive	Clinical setting	Mean age (range)	TP	FP	FN	TN	TP	FP	FN	TN
¹⁸F-FDG PET/CT
Koizumi M [30]	Japan	2019	120	-	No	No	Yes	New + treated	-	34	8	1	77	-	-	-	-
Caglar M [26]	Turkey	2016	150	-	No	No	Yes	New + treated	52(27–85)	84	1	1	64	-	-	-	-
Hahn S [22]	Germany	2011	28	129	No	No	Yes	New + treated	57.5(35–78)	7	0	1	20	67	5	3	54
Damle NA[15]	India	2013	72	-	Yes	No	Yes	Treated	52(30–77)	25	1	9	37	-	-	-	-
Al-Muqbel KM[25]	Jordan	2017	35	-	No	No	Yes	Treated	48.1	25	0	9	1	-	-	-	-
Botsikas D[34]	Switzerland	2019	80	175	Yes	No	Yes	New + treated	48	6	0	3	71	18	0	8	149
Rager O[24]	Switzerland	2018	25	109	No	Yes	Yes	New	55(38–82)	10	0	2	13	43	0	48	18
Heusner TA[28]	Germany	2010	20	-	Yes	No	Yes	New + treated	54.5(25.4–78.2)	7	0	0	13	-	-	-	-
Teke F[32]	Turkey	2015	-	496	No	No	-	New	44.5(28–81)	-	-	-	-	141	2	10	343
¹⁸F-NaF PET/CT
Yoon SH[33]	Korea	2013	119	-	Yes	No	-	New + treated	55.6	49	36	3	31	-	-	-	-
Broos WAM[23]	Netherlands	2018	118	-	Yes	No	-	New + treated	64	50	6	2	60	-	-	-	-
Damle NA[15]	India	2013	72	-	Yes	No	Yes	Treated	52	34	11	0	27	-	-	-	-
Passah A[29]	India	2017	-	199	Yes	No	-	New	43.8	-	-	-	-	178	0	0	21
Abikhzer G[31]	UK	2016	41	284	Yes	No	-	New + treated	58 (30–75)	21	3	0	17	73	6	7	198
Piccardo A [27]	Italy	2011	39	662	Yes	-	-	Treated	60	27	0	0	12	491	11	51	109

Diagnostic accuracy

A total of 9 studies using ¹⁸F-FDG PET/CT method had a sensitivity of 0.47 [95%CI: 0.37–0.58] to 1.0[95%CI:0.59-1.00] for the identification of breast cancer BM, and a specificity was 0.92 [95%CI:0.81–0.97] to 1.0 [95%CI:0.98 -1.00]. The pooled sensitivity and specificity of ¹⁸F-FDG PET/CT in the identification of BM from breast cancer were 0.88 [95% CI:0.76–0.94] and 0.99 [95% CI: 0.97-1.00], respectively, as shown in Fig. 2. Both Cochran’s Q test and Higgins I² test showed significant heterogeneity in sensitivity (Q = 168.81, p ≤ 0.01; I² = 93.48) and specificity (Q = 44.38, p ≤ 0.01; I² = 75.21). A total of 6 studies included ¹⁸F-NaF PET/CT in the detection of breast cancer BM, of which sensitivity and specificity ranged from 0.91 (95% CI: 0.83–0.96) to 1.00 (95% CI: 0.83–0.96), and 0.46 (95% CI: 0.34–0.59) to 1.00 (95% CI: 0.74-1.00), respectively. The pooled sensitivity and specificity were 0.98 (95% CI: 0.92–1.00) and 0.91 (95% CI: 0.76–0.97), respectively, as shown in Fig. 3. In addition, Cochran’s test and Higgins I² test also showed heterogeneity in sensitivity and specificity between studies, (Q = 70.87, p ≤ 0.01; I² = 90.12) and (Q = 228.86, p ≤ 0.01; I² = 96.94). The pooled PLR and NLR for ¹⁸F-FDG PET/CT were 129.2 (95% CI: 27.1-616.4) and 0.13 (95% CI: 0.06–0.25), respectively. On ¹⁸F-NaF PET/CT, the pooled PLR and NLR were 10.9 (95% CI: 3.8–31.5) and 0.02 (95% CI: 0.01–0.1), respectively. The pooled DOR value of ¹⁸F-FDG PET/CT for the diagnosis of breast cancer BM was 1028 (95% CI: 244–4330), and the pooled DOR value of ¹⁸F-NaF PET/CT was 489 (95% CI: 65-3654), as shown in Table 2. Analyses were performed by the dersimonan-laird method (random-effects model) with 95% CIs to calculate weighted mean pooled sensitivity, specificity, PLR, NLR and DOR (CIs). Variability was assessed graphically by plotting metrics with 95% CIs separately in each study in the forest plot. Values of pooled PLR greater than 10 and DOR greater than 100 indicate that a positive result for a given test helps to confirm the presence of BM, while pooled NLR values less than 0.1 indicate that a negative result helps to exclude BM [36]. Combined with our data, a positive result from the FDG assay helps to confirm the presence of BM and a negative result from the NaF assay helps to rule out BM. There was no significant difference in the DOR between ¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT. The area under the SROC curve for both ¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT was 0.99 (95%CI: 0.98 − 0.1.00), as shown in Fig. 4.

Table 2

Summary of diagnostic performance characteristics of ¹⁸F-FDG and ¹⁸F-NaF PET/CT in breast cancer bone metastases
Parameter	¹⁸F-FDG PET/CT		¹⁸F-NaF PET/CT
Parameter	Estimate	95% CI	Estimate	95% CI
Sensitivity	0.88	0.76, 0.94	0.98	0.92, 1.00
Specificity	0.99	0.97, 1.00	0.91	0.76, 0.97
Positive Likelihood Ratio	129.2	27.1, 616.4	10.9	3.8, 31.5
Negative Likelihood Ratio	0.13	0.06, 0.25	0.02	0.01, 0.1
Diagnostic Odds Ratio	1028	244, 4330	489	65, 3654
AUC	0.99	0.98, 1.00	0.99	0.98, 1.00
Notes:18F-FDG = Fluorine-18 labeled deoxyglucose; 18F-NaF = Fluorine-18 labeled sodium fluoride ; PET = Positron emission computer; CT = Computed tomography; CI = confidence interval; AUC = area under curve.

Publication bias

A funnel plot for publication bias for ¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT by Deeks et al. is shown in Fig. 5. The p value of slope coefficient for ¹⁸F-FDG PET/CT is less than 0.05 (p = 0.02), suggesting publication bias. The p value of slope coefficient for ¹⁸F-NaF PET/CT was 0.37, indicating a low possibility of study publication bias (p > 0.05).

Exploration of heterogeneity

The results of meta-regression analysis are shown in Table 3. A total of 8 studies reported patient-based results of the diagnostic performance of ¹⁸F-FDG PET/CT for breast cancer BM with a sensitivity of 0.89 (95% CI: 0.80–0.99) and a specificity of 0.99 (95% CI: 0.98-1.00), and 4 studies including 1038 lesions were lesion-based with a sensitivity of 0.84 (95% CI: 0.67-1.00) and specificity of 1.00 (95% CI: 0.98-1.00). In 7 studies with patients’ mean age > 50 years old, sensitivity was 0.88 (95% CI: 0.78–0.99), and specificity was 0.98 (95% CI: 0.96-1.00), respectively. Four studies with patients’ mean age less than 50 years old had sensitivity of 0.80 (95% CI: 0.60–0.99) and specificity of 1.00 (95% CI: 0.99-1.00). Neither the patient or the patient nor the mean age of the patients were responsible for the heterogeneity between studies, with a p value greater than 0.05. The study design, sample size, scan minimum slice thickness, attenuation correction, and machine source company are the sources of heterogeneity in the diagnostic performance of ¹⁸F- FDG-PET/CT in breast cancer BM, with a p value less than 0.05.

Table 3

Meta-regression analysis results of ¹⁸F-FDG PET/CT on bone metastases of breast cancer
Parameter	Category	No. of studies	Sensitivity	p value	Specificity	p value
¹⁸F-FDG PET/CT
Based	patient	8	0.89[0.80–0.99]	0.88	0.99[0.98-1.00]	0.21
	lesions	4	0.84[0.67- 1.00]		1.00[0.98-1.00]
Design	Prospective	4	0.78[0.55- 1.00]	0.13	1.00[0.99-1.00]	0.00
	Retrospective	8	0.91[0.83–0.98]		0.99[0.97-1.00]
Mean age	≥ 50	7	0.88[0.78–0.99]	0.73	0.98[0.96-1.00]	0.38
	< 50	4	0.80[0.60–0.99]		1.00[0.99–1.00
Sample	> 50	4	0.91[0.81- 1.00]	0.65	0.98[0.95-1.00]	0.00
	≤ 50	4	0.87[0.71- 1.00]		1.00[1.00–1.00]
Vendor	GE	4	0.92[0.81-1.00]	0.82	1.00[0.99-1.00]	0.07
	Siemens	6	0.89[0.77-1.00]		1.00[0.99-1.00]
AC	yes	7	0.89[0.78-1.00]	0.85	1.00[0.98-1.00]	0.02
	no	5	0.86[0.72-1.00]		0.99[0.98-1.00]
Slice thickness	≥ 4 mm	4	0.90[0.76-1.00]	0.55	0.99[0.95-1.00]	0.08
	< 4 mm	4	0.83[0.64-1.00]		0.99[0.95-1.00]
Notes:¹⁸F-FDG = Fluorine-18 labeled deoxyglucose; PET = Positron emission computer; CT = Computed tomography; CI = confidence interval; AC = attenuation correction.

In the present meta-analysis, the diagnostic performance of ¹⁸F-NaF PET/CT and ¹⁸F-FDG PET/CT in breast cancer BM were compared, which covered 847 patients and 2054 lesions from 14 studies. The current results show that ¹⁸F-NaF PET/CT is more sensitive than ¹⁸F-FDG PET/CT for the detection of BM of breast cancer ( 98% vs 88%), while ¹⁸F-FDG PET/CT is more specific than ¹⁸F-NaF PET/CT (99% vs 91%), but not statistically different, suggesting that the two tracers, ¹⁸F-FDG and ¹⁸F-NaF, have good diagnostic performance (both AUC are 0.99 [95%CI: 0.98 − 0.1.00]) when used as PET/CT imaging for the detection of breast cancer BM.

¹⁸F-FDG PET/CT is a sensitive molecular imaging methods capable of diagnosing BM by increasing FDG uptake in growing metastatic cancer cells [37]. Previous meta-analysis studies have shown that ¹⁸F-FDG PET/CT has high diagnostic performance in lymph node metastasis, staging, efficacy evaluation and prognosis after chemotherapy in breast cancer patients [38–41]. Various tracers have benifits and disadvantages for PET/CT imaging. The results of our present meta-analysis included 9 studies with 530 patients and 909 lesions showed that ¹⁸F-FDG PET/CT has good diagnostic performance, similarly. As an osteophytic tracer, ¹⁸F-NaF has the desirable characteristics of high and rapid bone uptake accompanied by very rapid blood clearance, which results in a high bone-to-background ratio in a short time, so it can display areas of altered skeletal activity and become more and more common in the detection of bone lesions in recent years [42]. Previous studies have shown that ¹⁸F-NaF PET/CT can accurately detect BM in various malignant tumors, including the degree of BM and the choice of treatment, which is a good model for early and accurate detection of BM [15, 43]. Our meta-analysis included 6 ¹⁸F-NaF PET/CT studies’ results showed that it has higher sensitivity in breast cancer BM, but lower specificity than ¹⁸F-FDG PET/CT. This may be related to various benign diseases of new bone formation leading to increased NaF uptake, which may lead to more false positives [26]. Moreover, it is worth noting that since ¹⁸F-FDG not only shows high accuracy in the detection of BM, but also shows high accuracy in distant organ tissue metastasis and lymph node metastasis [38, 39]. The current meta-analysis results show that ¹⁸F-FDG and ¹⁸F-NaF have comparable accuracy in detecting BM in breast cancer, so ¹⁸F-FDG should be considered first in clinical practice, and additional ¹⁸F-NaF examination may not be necessary. Whereas, when there is doubt about the presence of BM on the ¹⁸F-FDG PETCT, and if the treatment options highly depend on this knowledge, ¹⁸F-NaF could be considered as second line imaging.

The current meta-analysis revealed heterogeneity in the pooled sensitivity and specificity for both ¹⁸F-FDG PET/CT and ¹⁸F-NaF PET/CT studies. The subgroup analysis showed the type of study design, sample size and whether to use attenuation correction technique are factors to assess heterogeneity among breast cancer BM studies. Specifically, the specificity of retrospective studies is not as high as that of prospective studies, possibly because the retrospective study design inherently leads to bias in patient selection. Moreover, studies with sample sizes less than 50 patients showed higher specificity, which may be related to the small sample size and the small number of false positives. In addition, the specificity of studies using attenuation correction for scanning techniques was higher than that without attenuation correction, which may be related to better image quality and clearer visualization of lesions after attenuation correction [44]. The meta-regression results showed that lesion-based analysis was more specific than patient-based analysis, and patients’ mean age < 50 years was more specific than > 50 years, but there were no statistical difference. Moreover, scan slice thickness was not a factor contributing to the heterogeneity between studies in this meta-analysis. Meta-regression analysis of ¹⁸F-NaF PET/CT was not possible because only 6 studies of ¹⁸F-NaF PET/CT met the inclusion criteria and were included for meta-analysis, and data from some of the studies were not available.

The main limitation of the current meta-analysis is that the number of eligible studies is relatively limited, especially the study of ¹⁸F-NaF PET/CT detection of breast cancer BM. It is worth mentioning that when we performed data extraction on the retrieved literature, we found that the TP, FP, FN and TN values provided by two articles contradicted the sensitivity and specificity, so we excluded them [45, 46]. Second, heterogeneity in the assessment of diagnostic accuracy among ¹⁸F-FDG-PET/CT and ¹⁸F-NaF PET/CT studies also limited the quality of the meta-analysis. Not all eligible patients had histopathological validation of BM in reference standards in the present meta-analysis, and imaging-based reference standards including CT, MRI as followed up, which may increase clinical heterogeneity, but obtained all skeletal histological evidence of lesions is impractical and unethical. Therefore, results by non-invasive imaging modalities that are not rigorously validated by histological examination are acceptable. The diagnostic performance of ¹⁸F-NaF PET/CT and ¹⁸F-FDG PET/CT in the detection of breast cancer BM were compared in the present study, but limited data may limit estimates of diagnostic efficacy. However, the diagnostic performance of ¹⁸F-NaF PET/CT and ¹⁸F-FDG PET/CT of the study in

detecting BM in breast cancer patients provides a reference for clinical practice and avoids the subjective interpretation of results.

In conclusion, this study shows that ¹⁸F-NaF PET/CT and ¹⁸F-FDG PET/CT are accurate methods for detecting BM in breast cancer patients, and the diagnostic accuracy of both is the same.

¹⁸F, Fluorine-18; BM, bone metastases, FDG, fluorodeoxyglucose; NaF, fluoride; PET/CT, Positron emission tomography/computed tomography; TP, true positive; FP, false positive; FN, false negative; TN, true negative; PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratio; SROC, summary receiver operating characteristic curve; AUC, area under the curve; CIs, confidence intervals.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests.

Funding

This study was funded by the National Natural Science Foundation of the People’s Republic of China, NSFC (Grant No. 82260353).

Author Contributions

XH and HH conceived and designed the structure of this manuscript. XH, ZL, WY and SL wrote the paper, JC and DL revised the paper. All authors have read and approved the final manuscript.

Acknowledgements

Not applicable.

Author details

¹Department of Nuclear Medicine, Affiliated Hospital of Zunyi Medical University, No.149 Dalian Road, Huichuan District, Zunyi, Guizhou Province, PR China 563003.

²Department of Obstetrics, Zunyi Hospital of Traditional Chinese Medicine, Zunyi, Guizhou, PR China 563003. Intersection of Donglian Line 2 and Zong’er Road, Xinpu New District, Zunyi, Guizhou Province, PR China 563003.

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.
Cook GJ, Houston S, Rubens R, Maisey MN, Fogelman I. Detection of bone metastases in breast cancer by 18FDG PET: differing metabolic activity in osteoblastic and osteolytic lesions. J Clin Oncol. 1998;16:3375–9.
Zengel B, Kilic M, Tasli F, Simsek C, Karatas M, Ozdemir O, Cavdar D, Durusoy R, Bas KK, Uslu A. Breast cancer patients with isolated bone metastases and oligometastatic bone disease show different survival outcomes. Sci Rep. 2021;11:20175.
Pantel K, Hayes DF. Disseminated breast tumour cells: biological and clinical meaning. Nat Rev Clin Oncol. 2018;15:129–31.
Makhoul I, Montgomery CO, Gaddy D, Suva LJ. The best of both worlds - managing the cancer, saving the bone. Nat Rev Endocrinol. 2016;12:29–42.
Brook N, Brook E, Dharmarajan A, Dass CR, Chan A. Breast cancer bone metastases: pathogenesis and therapeutic targets. Int J Biochem Cell Biol. 2018;96:63–78.
Weigelt B, Peterse, JL; van. 't Veer, L.J. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602.
Liu T, Cheng T, Xu W, Yan WL, Liu J, Yang HL. A meta-analysis of 18FDG-PET, MRI and bone scintigraphy for diagnosis of bone metastases in patients with breast cancer. Skeletal Radiol. 2011;40:523–31.
Cook GJ, Azad GK, Goh V. Imaging Bone Metastases in Breast Cancer: Staging and Response Assessment. J Nucl Med. 2016;57(Suppl 1):27S–33S.
Hansen JA, Naghavi-Behzad M, Gerke O, Baun C, Falch K, Duvnjak S, Alavi A, Høilund-Carlsen PF, Hildebrandt MG. Diagnosis of bone metastases in breast cancer: Lesion-based sensitivity of dual-time-point FDG-PET/CT compared to low-dose CT and bone scintigraphy. PLoS ONE. 2021;16:e0260066.
Garami Z, Hascsi Z, Varga J, Dinya T, Tanyi M, Garai I, Damjanovich L, Galuska L. The value of 18-FDG PET/CT in early-stage breast cancer compared to traditional diagnostic modalities with an emphasis on changes in disease stage designation and treatment plan. Eur J Surg Oncol. 2012;38:31–7.
Bastawrous S, Bhargava P, Behnia F, Djang DS, Haseley DR. Newer PET application with an old tracer: role of 18F-NaF skeletal PET/CT in oncologic practice. Radiographics. 2014;34:1295–316.
Xiong Z, Deng G, Huang X, Li X, Xie X, Wang J, et al. Bone metastasis pattern in initial metastatic breast cancer: a population-based study. Cancer Manag Res. 2018;10:287–95. doi:10.2147/CMAR.S155524.
Tsuzuki S, Park SH, Eber MR, Peters CM, Shiozawa Y. Skeletal complications in cancer patients with bone metastases. Int J Urol. 2016;23:825–32. doi:10.1111/iju.13170.
Damle NA, Bal C, Bandopadhyaya GP, Kumar L, Kumar P, Malhotra A, Lata S. The role of 18F-fluoride PET-CT in the detection of bone metastases in patients with breast, lung and prostate carcinoma: a comparison with FDG PET/CT and 99mTc-MDP bone scan. Jpn J Radiol. 2013;31:262–9.
Al-Muqbel KM, Yaghan RJ, Al-Omari MH, Rousan LA, Dagher NM, Al Bashir S. Clinical relevance of 18F-FDG-negative osteoblastic metastatic bone lesions noted on PET/CT in breast cancer patients. Nucl Med Commun. 2016;37:593–601. doi:10.1097/MNM.0000000000000481.
Gaeta CM, Vercher-Conejero JL, Sher AC, Kohan A, Rubbert C, Avril N. Recurrent and metastatic breast cancer PET, PET/CT, PET/MRI: FDG and new biomarkers. Q J Nucl Med Mol Imaging. 2013;57:352–66.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ (Clinical research ed.) 2009, 339, b2700.
Whiting PF, Rutjes AW, Westwood ME, Mallett S, Deeks JJ, Reitsma JB, Leeflang MM, Sterne JA, Bossuyt PM. QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med. 2011;155:529–36.
Ioannidis JP. Interpretation of tests of heterogeneity and bias in meta-analysis. J Eval Clin Pract. 2008;14:951–7.
Deeks JJ, Macaskill P, Irwig L. The performance of tests of publication bias and other sample size effects in systematic reviews of diagnostic test accuracy was assessed. J Clin Epidemiol. 2005;58:882–93.
Hahn S, Heusner T, Kümmel S, Köninger A, Nagarajah J, Müller S, Boy C, Forsting M, Bockisch A, Antoch G, et al. Comparison of FDG-PET/CT and bone scintigraphy for detection of bone metastases in breast cancer. Acta Radiol. 2011;52:1009–14.
Broos W, van der Zant FM, Wondergem M, Knol R. Accuracy of 18F-NaF PET/CT in bone metastasis detection and its effect on patient management in patients with breast carcinoma. Nucl Med Commun. 2018;39:325–33.
Rager O, Lee-Felker SA, Tabouret-Viaud C, Felker ER, Poncet A, Amzalag G, Garibotto V, Zaidi H, Walter MA. Accuracy of whole-body HDP SPECT/CT, FDG PET/CT, and their combination for detecting bone metastases in breast cancer: an intra-personal comparison. Am J Nucl Med Mol Imaging. 2018;8:159–68.
Al-Muqbel KM Bone Marrow Metastasis Is an Early Stage of Bone Metastasis in Breast Cancer Detected Clinically by F18-FDG-PET/CT Imaging. Biomed Res Int 2017, 2017, 9852632.
Caglar M, Kupik O, Karabulut E, Høilund-Carlsen PF. Detection of bone metastases in breast cancer patients in the PET/CT era: Do we still need the bone scan. Revista Esp de Med Nuclear e Imagen Mol. 2016;35:3–11.
Piccardo A, Altrinetti V, Bacigalupo L, Puntoni M, Biscaldi E, Gozza A, Cabria M, Iacozzi M, Pasa A, Morbelli S, et al. Detection of metastatic bone lesions in breast cancer patients: fused (18)F-Fluoride-PET/MDCT has higher accuracy than MDCT. Preliminary experience. Eur J Radiol. 2012;81:2632–8.
Heusner TA, Kuemmel S, Koeninger A, Hamami ME, Hahn S, Quinsten A, Bockisch A, Forsting M, Lauenstein T, Antoch G, et al. Diagnostic value of diffusion-weighted magnetic resonance imaging (DWI) compared to FDG PET/CT for whole-body breast cancer staging. Eur J Nucl Med Mol Imaging. 2010;37:1077–86.
Passah A, Tripathi M, Ballal S, Yadav MP, Kumar R, Roesch F, Meckel M, Sarathi Chakraborty P, Bal C. Evaluation of bone-seeking novel radiotracer (68)Ga-NO2AP-Bisphosphonate for the detection of skeletal metastases in carcinoma breast. Eur J Nucl Med Mol Imaging. 2017;44:41–9.
Koizumi M, Motegi K, Umeda T. A novel biomarker, active whole skeletal total lesion glycolysis (WS-TLG), as a quantitative method to measure bone metastatic activity in breast cancer patients. Ann Nucl Med. 2019;33:502–11.
Abikhzer G, Srour S, Fried G, Drumea K, Kozlener E, Frenkel A, Israel O, Fogelman I, Kagna O. Prospective comparison of whole-body bone SPECT and sodium 18F-fluoride PET in the detection of bone metastases from breast cancer. Nucl Med Commun. 2016;37:1160–8.
Teke F, Teke M, Inal A, Kaplan MA, Kucukoner M, Aksu R, Urakci Z, Tasdemir B, Isikdogan A. Significance of hormone receptor status in comparison of 18F -FDG-PET/CT and 99mTc-MDP bone scintigraphy for evaluating bone metastases in patients with breast cancer: single center experience. Asian Pac J Cancer Prev. 2015;16:387–91.
Yoon SH, Kim KS, Kang SY, Song HS, Jo KS, Choi BH, Lee SJ, Yoon JK, An YS. Usefulness of (18)F-fluoride PET/CT in Breast Cancer Patients with Osteosclerotic Bone Metastases. Nucl Med Mol Imaging. 2013;47:27–35.
Botsikas D, Bagetakos I, Picarra M, Da CA Barisits, Boudabbous AC, Montet S, Lam X, Mainta GT, Kalovidouri I, Becker A. 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.
Hu X, Li D, Liang Z, Liao Y, Yang L, Wang R, et al. Indirect comparison of the diagnostic performance of (18)F-FDG PET/CT and MRI in differentiating benign and malignant ovarian or adnexal tumors: a systematic review and meta-analysis. BMC Cancer. 2021;21(1):1080. https://doi.org/10.1186/s12885-021-08815-3.
Deeks JJ. Systematic reviews in health care: Systematic reviews of evaluations of diagnostic and screening tests. BMJ (2001) 323:157 – 62. doi: 10.1136/bmj.323.7305.157.
Evangelista L, Panunzio A, Polverosi R, Ferretti A, Chondrogiannis S, Pomerri F, Rubello D, Muzzio PC. Early bone marrow metastasis detection: the additional value of FDG-PET/CT vs. CT imaging. 66: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie; 2012. pp. 448–53.
Han S, Choi JY. Impact of 18F-FDG PET, PET/CT, and PET/MRI on Staging and Management as an Initial Staging Modality in Breast Cancer: A Systematic Review and Meta-analysis. Clin Nucl Med. 2021;46:271–82.
Zhang X, Liu Y, Luo H, Zhang J. PET/CT and MRI for Identifying Axillary Lymph Node Metastases in Breast Cancer Patients: Systematic Review and Meta-Analysis. J Magn Reson Imaging. 2020;52:1840–51.
Han S, Choi JY. Prognostic value of (18)F-FDG PET and PET/CT for assessment of treatment response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. Breast Cancer Res. 2020;22:119.
Diao W, Tian F, Jia Z. The prognostic value of SUV(max) measuring on primary lesion and ALN by (18)F-FDG PET or PET/CT in patients with breast cancer. Eur J Radiol. 2018;105:1–7.
Grant FD, Fahey FH, Packard AB, Davis RT, Alavi A, Treves ST. Skeletal PET with 18F-fluoride: applying new technology to an old tracer. J Nucl Med. 2008;49:68–78.
Schirrmeister H, Guhlmann A, Kotzerke J, Santjohanser C, Kühn T, Kreienberg R, Messer P, Nüssle K, Elsner K, Glatting G, et al. Early detection and accurate description of extent of metastatic bone disease in breast cancer with fluoride ion and positron emission tomography. J Clin Oncol. 1999;17:2381–9.
Bebbington NA, Zacho HD, Holdgaard PC. Lesion detection in 18F-sodium fluoride bone imaging: a comparison of attenuation-corrected versus nonattenuation-corrected PET reconstructions from modern PET-CT systems. Nucl Med Commun. 2022;43:78–85. doi:10.1097/MNM.0000000000001487.
Capitanio S, Bongioanni F, Piccardo A, Campus C, Gonella R, Tixi L, Naseri M, Pennone M, Altrinetti V, Buschiazzo A, et al. Comparisons between glucose analogue 2-deoxy-2-((18)F)fluoro-D-glucose and (18)F-sodium fluoride positron emission tomography/computed tomography in breast cancer patients with bone lesions. World J Radiol. 2016;8:200–9.
Balci TA, Koc ZP, Komek H. Bone scan or (18)f-fluorodeoxyglucose positron emission tomography/computed tomography; which modality better shows bone metastases of breast cancer. Breast care (Basel Switzerland). 2012;7:389–93.

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The diagnostic performance of ¹⁸F-FDG PET/CT versus ¹⁸F-NaF PET/CT in breast cancer with bone metastases: an indirect comparative meta-analysis

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