Quantitative ^99mTc-MDP SPECT/CT for predicting neoadjuvant chemotherapy efficacy in osteosarcoma

Introduction

Osteosarcoma (OS) is one of the most common primary malignant bone tumors, typically characterized by high invasiveness and poor prognosis (1). Fortunately, the application of neoadjuvant chemotherapy (NACT) has greatly improved the prognosis of patients with OS, and the 5-year survival rate has increased from less than 20% to more than 60% (2). Furthermore, the positive effect of NACT has led to a major shift from amputation to limb salvage surgery and improved patients’ quality of life (3).

Early evaluation of NACT efficacy has important implications for prognosis assessment and treatment selection, and good NACT efficacy is related to favorable outcomes in patients with OS (4,5). Histological necrosis rate is regarded as the reference standard for assessing NACT efficacy (6); however, it is only available after the postoperative pathological evaluation, by which stage it is too late to adjust the NACT regimen. Hence, the preoperative noninvasive prediction of NACT efficacy is extremely important. The predictive value of positron emission tomography/computed tomography (PET/CT) has previously been reported (7), but its limitations include relatively low availability and high cost. Therefore, it remains challenging to predict NACT efficacy in a timely and noninvasive manner.

^99mTechnetium-methylene diphosphonate (^99mTc-MDP) bone scanning is widely used in diagnosis and management of OS, and it has proven useful in assessing efficacy (8-10). However, conventional bone scans provide planar imaging without quantitative information, resulting in limited objectivity and reproducibility. Single photon emission computed tomography/computed tomography (SPECT/CT) is a well-established and widely available imaging technique. With new technological advances, maximum standardized uptake value (SUVmax), originally developed for PET/CT semi-quantification, can now be measured by advanced quantitative SPECT/CT (11). At present, research on the value of quantitative ^99mTc-MDP SPECT/CT for predicting NACT efficacy in OS is limited. Therefore, the purpose of our study was to assess the predictive value of quantitative ^99mTc-MDP SPECT/CT in predicting NACT efficacy in OS. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1890/rc).

Methods

Patients

We retrospectively collected all OS patients from February 2019 to February 2025 at Beijing Jishuitan Hospital, Capital Medical University. The inclusion criteria were as follows: OS was determined by pathological diagnosis before NACT; patients received surgical treatment with histological necrosis rate assessment after NACT; and ^99mTc-MDP bone scans and quantitative ^99mTc-MDP SPECT/CT were performed before and after NACT. The exclusion criteria were as follows: complicated with pathologic fractures; underwent any treatment before initial imaging; received radiotherapy before surgery; incomplete clinical or imaging data; and unsatisfactory image quality. NACT regimens involved methotrexate (1st), cisplatin and adriamycin (2nd), ifosfamide (3rd), and methotrexate (4th) (12). All pathological specimens were diagnosed independently by two pathologists, who were be blinded to imaging results. Before treatment and scanning, all patients underwent biopsy and were classified according to World Health Organization (WHO) 2020 classification (13). The NACT efficacy was assessed as good (histological necrosis rate >90%) and poor (histological necrosis rate <90%) based on postoperative pathology (14). Staging was performed according to the American Joint Committee on Cancer recommendation (1).

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by the patients or their guardians. The study was approved by Research Ethics Committee of Beijing Jishuitan Hospital, Capital Medical University.

Image acquisition

All patients underwent ^99mTc-MDP bone scans and quantitative ^99mTc-MDP SPECT/CT (Discovery 670 Pro, GE HealthCare, Chicago, IL, USA) according to the recommended protocol of the manufacturer. The dosage of ^99mTc-MDP was based on body weight and age, in accordance with the European Association of Nuclear Medicine (EANM) practice guideline (15). Whole-body planar bone scans were acquired in anterior and posterior views with a low-energy high-resolution collimator 3 hours after injection. The planar scan parameters were as follows: matrix, 1,024×256; speed, 15 cm/min; energy peak, 140 keV; energy window, ±10%. Quantitative SPECT/CT scans were performed immediately after planar scanning. SPECT images were obtained with parameters as follows: matrix, 128×128; speed, 12 s/frame; energy peak, 140 keV; energy window, ±10%. Then, CT images were obtained for attenuation correction and anatomical reference with the following parameters: tube voltage, 120 kV; tube current, 100 mA; slice thickness, 5.0 mm; pitch, 1.375; reconstruction interval, 5.0 mm. CT images were reconstructed into 2.5 mm-thick transaxial slices, and SPECT images were reconstructed using ordered subset expectation maximization (OSEM; 2 iterations and 10 subsets).

Image analysis

All ^99mTc-MDP bone scans and quantitative ^99mTc-MDP SPECT/CT images were reviewed by two experienced nuclear medicine physicians who were blinded to the pathological results. For planar images, the region of interest (ROI) of the primary tumor was manually delineated on workstation (Xeleris version 4.0, GE HealthCare), and the maximum pixel count of the ROI was obtained (anterior image, TAmax; posterior image, TPmax). As reference, a similarly sized ROI was drawn in the contralateral nontumor area (anterior image, NTAmax; posterior image, NTPmax). The maximum tumor/nontumor radioactive count (T/NTmax; before NACT, Pre-T/NTmax; after NACT, Post-T/NTmax) was calculated using the following formula (16): T/NTmax=TAmax×TPmax/NTAmax×NTPmax. The percentage change of T/NTmax was calculated using the following formula: ΔT/NTmax = 100% × (Post-T/NTmax − Pre-T/NTmax)/Pre-T/NTmax.

For quantitative ^99mTc-MDP SPECT/CT images, the volume of interest (VOI) was defined using semi-automated adaptive threshold delineation of primary tumor radioactivity in Q metrix software (GE HealthCare). SUVmax (before NACT, Pre-SUVmax; after NACT, Post-SUVmax) was calculated automatically. The percentage change of SUVmax was calculated using the following formula: ΔSUVmax = 100% × (Post-SUVmax − Pre-SUVmax)/Pre-SUVmax. A negative ΔT/NTmax or ΔSUVmax value indicated a reduction in radioactivity after NACT, whereas a positive value indicated an increase. The absolute value of ΔT/NTmax orΔSUVmax reflected the extent of the change, regardless of direction.

Statistical analysis

Qualitative variables were described as counts and percentages and were tested by chi-square test or Fisher’s exact test. Non-normal distributed continuous variables were summarized as median with interquartile range and were tested by Mann-Whitney test. Comparisons of continuous variables between good and poor efficacy groups were performed using Mann-Whitney test. The area under the curve (AUC) was obtained by receiver operating characteristic (ROC) curve analysis. The optimal cut-off value was determined using the Youden index (sensitivity + specificity − 1). Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with a 95% confidence interval (CI). Delong test was conducted to assess the difference between ROC curves. The threshold for significance was set at P=0.05. Data were statistically analyzed using R software version 4.0.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Clinical characteristics

After screening 79 potential patients, 67 patients were enrolled in the study, including 26 patients with good efficacy and 41 patients with poor efficacy. The flowchart of patients is presented in Figure 1, and the clinical characteristics of patients are displayed in Table 1. There were no significant differences in clinical or demographic variables between the good and poor efficacy groups, including age, gender, stage, pathological subtype, and location of tumor.

Figure 1 Flowchart of patient inclusion and exclusion.

Comparison of ^99mTc-MDP bone scan and quantitative ^99mTc-MDP SPECT/CT between the good and poor efficacy groups

The ^99mTc-MDP bone scan and quantitative ^99mTc-MDP SPECT/CT findings are displayed in Table 2 and Figure 2. The post-SUVmax value was significantly lower in the good efficacy group than that in poor efficacy group [19.1 (7.4, 37.3) vs. 34.9 (21.6, 60.8), P=0.006]. The good efficacy group showed significantly greater reductions in ΔT/NTmax [–20.2% (–37.7%, 1.7%) vs. 24.3% (–18.9%, 77.1%), P=0.004] and ΔSUVmax [–32.5% (–60.3%, –13.3%) vs. 21.0% (–11.0%, 48.3%), P<0.001] compared to the poor efficacy group (Negative ΔT/NTmax or ΔSUVmax values indicate a post-treatment decrease, whereas a positive value indicates an increase. The absolute value represents the extent of the change). There were no statistically significant differences in Pre-T/NTmax, Post-T/NTmax, or Pre-SUVmax between the two groups.

Figure 2 Comparison of ^99mTc-MDP bone scan and quantitative ^99mTc-MDP SPECT/CT between good and poor efficacy groups of OS patients. No statistically significant differences were observed in Pre-T/NTmax (P=0.928), Post-T/NTmax (P=0.085) or Pre-SUVmax (P=0.969) between the good efficacy and poor efficacy groups. Post-SUVmax (P=0.006), ΔT/NTmax (P=0.004), and ΔSUVmax (P<0.001) differed significantly between two groups. *, P<0.01; **, P<0.001. ^99mTc-MDP, ^99mTechnetium-methylene diphosphonate; ns, no statistical significance; OS, osteosarcoma; SPECT/CT, single photon emission computed tomography/computed tomography; SUVmax, maximum standardized uptake value; T/NTmax, maximum tumor/nontumor radioactive count.

The predictive performance of ^99mTc-MDP bone scan and quantitative ^99mTc-MDP SPECT/CT between the good and poor efficacy groups

The predictive performance of ^99mTc-MDP bone scan and quantitative ^99mTc-MDP SPECT/CT is presented in Table 3 and Figure 3. ROC curves indicated that Post-SUVmax, ΔT/NTmax, and ΔSUVmax had relatively good predictive performance. Post-SUVmax, with a cut-off value of 23.5, showed an AUC of 0.699 (95% CI: 0.569–0.829), accuracy of 0.716 (95% CI: 0.593–0.820), sensitivity of 0.756 (95% CI: 0.597–0.876), specificity of 0.654 (95% CI: 0.443–0.828), PPV of 0.775 (95% CI: 0.664–0.857), and NPV of 0.630 (95% CI: 0.481–0.757). ΔT/NTmax, with a cut-off value of 5.8%, showed an AUC of 0.712 (95% CI: 0.586–0.838), accuracy of 0.701 (95% CI: 0.577–0.807), sensitivity of 0.610 (95% CI: 0.445–0.758), specificity of 0.846 (95% CI: 0.651–0.956), PPV of 0.862 (95% CI: 0.711–0.941), and NPV of 0.579 (95% CI: 0.476–0.676). ΔSUVmax, with a cut-off value of –12.7%, showed an AUC of 0.811 (95% CI: 0.701–0.920), accuracy of 0.806 (95% CI: 0.691–0.892), sensitivity of 0.805 (95% CI: 0.651–0.912), specificity of 0.808 (95% CI: 0.606–0.934), PPV of 0.868 (95% CI: 0.747–0.936), and NPV of 0.724 (95% CI: 0.578–0.834). Delong test was used to compare the predictive ability of Post-SUVmax, ΔT/NTmax, and ΔSUVmax, and the results are presented in Table 4. ΔSUVmax showed a significantly higher AUC than that of ΔT/NTmax (0.811 vs. 0.712, P=0.021), representing higher predictive value. Although no statistical significance was found between ΔSUVmax and Post-SUVmax, the AUC of ΔSUVmax was higher than that of Post-SUVmax, and the P value was close to 0.05 (0.811 vs. 0.699, P=0.061). Comparison between ΔT/NTmax and Post-SUVmax did not reveal any significant difference (0.712 vs. 0.699, P=0.866).

Figure 3 ROC curves of ^99mTc-MDP bone scan and quantitative ^99mTc-MDP SPECT/CT parameters. (A) ROC curve of Pre-T/NTmax; (B) ROC curve of Post-T/NTmax; (C) ROC curve of Pre-SUVmax; (D) ROC curve of Post-SUVmax; (E) ROC curve of △T/NTmax; (F) ROC curve of △SUVmax. ^99mTc-MDP, ^99mTechnetium-methylene diphosphonate; ROC, receiver operating characteristic; SPECT/CT, single photon emission computed tomography/computed tomography; SUVmax, maximum standardized uptake value; T/NTmax, maximum tumor/nontumor radioactive count.

Discussion

Our study showed that both ^99mTc-MDP bone scan and quantitative ^99mTc-MDP SPECT/CT could predict the NACT efficacy in patients with OS, and decreased ^99mTc-MDP uptake after NACT compared with that before NACT indicated good efficacy (Figure 4). Notably, our study found that quantitative ^99mTc-MDP SPECT/CT had a better predictive value than planar scan.

Figure 4 An OS case of the left distal femur. A 13-year-old boy presented with pain in the left knee. ^99mTc-MDP bone scan and quantitative SPECT/CT showed distal femoral OS with high ^99mTc-MDP uptake. After NACT treatment, the decrease of ^99mTc-MDP radioactive distribution in tumor decreased was not significant on planar image (ΔT/NTmax =−7.0%, black arrows), but it was significant on quantitative SPECT/CT (ΔSUVmax =−27.2%, white arrows). Postoperative pathological results indicated that the efficacy of NACT was good (A,B: before NACT; C,D: after NACT). ^99mTc-MDP, ^99mTechnetium-methylene diphosphonate; NACT, neoadjuvant chemotherapy; OS, osteosarcoma; SPECT/CT, single photon emission computed tomography/computed tomography; SUVmax, maximum standardized uptake value; T/NTmax, maximum tumor/nontumor radioactive count.

^99mTc-MDP bone scan has frequently been performed for the initial staging, restaging, and follow-up of patients with OS (17). Most OS lesions are characterized by intense osteoblastic activity. ^99mTc-MDP bone scan capitalizes on this property by detecting regions of overactive osteoblasts, resulting in high diagnostic sensitivity. In comparison to PET/CT, bone scan is less expensive, more readily available, and involves a lower radiation exposure. Although ^99mTc-MDP bone scan has been extensively used in OS, several challenges remain. First, nuclear medicine physicians’ visual assessment of planar images may lead to less reliable conclusions. To improve reliability, previous studies calculated T/NTmax, defined as the maximum pixel counts of tumor to nontumor ratio (16,18). However, planar images cannot provide precise anatomical information; some OS lesions may be poorly demarcated from surrounding normal bone tissue, which may result in inaccurate counts of tumor ROIs. Third, OS often occurs in the metaphysis of childrens’ and adolescents’ long bones, and these regions show increased uptake of ^99mTc-MDP physiologically (19,20). In some challenging cases, when a metaphyseal tumor is small or shows moderate ^99mTc-MDP uptake, the measured counts of tumor ROIs may reflect physiological uptake in the metaphysis rather than tumor activity (17).

The semiquantitative metabolic parameters derived from PET/CT, such as SUVmax, have been reported to be useful in assessing response to NACT in OS patients (21). Recent technological advances allow SPECT/CT to incorporate PET/CT system techniques, including attenuation correction, scatter compensation, and resolution recovery (11). Unlike traditional nuclear medicine examinations, SUVmax measured by quantitative SPECT/CT offers the advantages of high accuracy, convenient measurement, and good repeatability (22). Furthermore, quantitative SPECT/CT provides precise tumor localization and effectively reduces interference from overlapping anatomical structures. Gherghe et al. found that quantitative SPECT/CT could assess the treatment response in bone metastases (23). Currently, only one published case report has used quantitative SPECT/CT to assess NACT efficacy in OS patients (24). In our study, ΔSUVmax showed better performance than ΔT/NTmax for prediction (AUC =0.811 vs. 0.712, P=0.021). In some cases where lesions were located in the metaphyseal region, ΔSUVmax accurately predicted therapeutic response whereas ΔT/NTmax failed, likely due to confounding physiological uptake in metaphysis (Figure 5). Compared with bone scan, quantitative ^99mTc-MDP SPECT/CT can assess neoplastic ^99mTc-MDP uptake more accurately to predict the response of OS to NACT.

Figure 5 Another OS case of the left distal femur. A 9-year-old boy presented with pain in the left knee. ^99mTc-MDP bone scan (black arrows) and quantitative SPECT/CT (white arrows) showed distal femoral OS with moderate ^99mTc-MDP uptake. The tumor located in the metaphyseal region, and a part of ^99mTc-MDP uptake was confounded by physiological uptake in metaphysis on planar image. The ΔT/NTmax was smaller than cut-off value (–38.2%, cut-off value = 5.8%), indicating that the efficacy of NACT was good. However, ΔSUVmax was bigger than cut-off value (–11.0%, cut-off value = –12.7%), indicating that the efficacy was poor. Postoperative pathological results indicated that the efficacy was poor (A,B: before NACT; C,D: after NACT). ^99mTc-MDP, ^99mTechnetium-methylene diphosphonate; NACT, neoadjuvant chemotherapy; OS, osteosarcoma; SPECT/CT, single photon emission computed tomography/computed tomography; SUVmax, maximum standardized uptake value; T/NTmax, maximum tumor/nontumor radioactive count.

To acquire the variation of ^99mTc-MDP uptake, patients need undergo bone scans and quantitative SPECT/CT twice, at diagnosis and following NACT. However, repeated imaging comes with the disadvantages of high cost and increased radiation exposure. Cumulative radiation exposure from repeated imaging is assumed to increase the risk of adverse health effects, especially in pediatric patients (25). In addition, some patients may receive imaging on different devices, and the differences in devices or protocols make the comparisons less reliable over time. The SUVmax obtained from PET/CT has been shown to predict the histological response alone, whereas SUVmax obtained from quantitative SPECT/CT has not been studied (21). In our study, Post-SUVmax has comparable predictive value to that of ΔT/NTmax (AUC =0.699 vs. 0.712, P=0.866). Our results indicated that single quantitative ^99mTc-MDP SPECT/CT scan has comparable predictive value to repeated planar bone scans, which has the potential to reduce the cost and radiation exposure. Moreover, it is worth noting that ΔSUVmax had a bigger AUC than Post-SUVmax, with a P value close to statistical significance (AUC =0.811 vs. 0.699, P=0.061). More studies with sufficient samples are needed to compare the predictive value of single and repeated quantitative ^99mTc-MDP SPECT/CT.

Our study had some limitations. First, this was a retrospective single-center study with a small population and an inevitable bias. Patients whose tumor had shrunk significantly after NACT tended to undergo only planar bone scan without quantitative ^99mTc-MDP SPECT/CT to reduce the cost. Thus, there were more patients with poor efficacy included in this study than there were those with good efficacy. Second, in some OS patients responding to NACT, SUVmax may increase due to the flare phenomenon, which may result in a decrease on the predictive power of SUVmax (16). Third, due to software limitations, other quantitative parameters, such as metabolic bone volume (MBV) and total bone uptake (TBU), were not included in this study. Based on these limitations, multicenter prospective studies with larger sample and more parameters are needed to verify our results.

Conclusions

Our study found that quantitative ^99mTc-MDP SPECT/CT is an efficient technique for predicting NACT efficacy in OS. Quantitative ^99mTc-MDP SPECT/CT has better predictive ability than planar bone scan.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1890/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1890/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1890/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was collected from patients or patients’ guardians. The study was approved by Research Ethics Committee of Beijing Jishuitan Hospital, Capital Medical University.

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

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