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. 2018 Sep 14;97(37):e12318. doi: 10.1097/MD.0000000000012318

Comparison of 99mTc-methyl diphosphonate bone scintigraphy and 18F-fluorodeoxyglucose positron emission tomography/computed tomography to predict histologic response to neoadjuvant chemotherapy in patients with osteosarcoma

Inki Lee a, Byung Hyun Byun a, Ilhan Lim a, Byung Il Kim a, Chang-Bae Kong b,∗, Won Seok Song b, Wan Hyeong Cho b, Jae-Soo Koh c, Sang Moo Lim a,∗
Editor: Dwight M Achong
PMCID: PMC6155965  PMID: 30212975

Abstract

We compared the usefulness of 99mTc-methyl diphosphonate (99mTc-MDP) bone scintigraphy and 18F-fluorodeoxyglucose (FDG) for positron emission tomography/computed tomography (PET/CT) in predicting histologic response in patients with osteosarcoma receiving neoadjuvant chemotherapy (NAC).

We retrospectively reviewed 62 patients with high-grade osteosarcoma who had received 2 cycles of NAC and surgery. All patients underwent 99mTc-MDP bone scintigraphy and 18F-FDG PET/CT before and after NAC. 99mTc-MDP uptake in the primary tumor was measured quantitatively as the maximum tumor-to-nontumor ratio (T/NTmax) and 18F-FDG uptake was measured as the maximum standardized uptake value (SUVmax), before and after NAC. The percent changes of T/NTmax (percent changes of the maximum tumor-to-nontumor ratio [Δ%T/NTmax]) and SUVmax (percent changes of the maximum standardized uptake value [Δ%SUVmax]) after NAC were calculated and the correlations between these parameters were evaluated. After surgery, the effects of NAC were graded histopathologically (good vs poor) and the optimum cut-off values of Δ%T/NTmax and Δ%SUVmax for predicting histologic response were assessed using the receiver operating characteristic (ROC) curve analysis.

Δ%T/NTmax and Δ%SUVmax were positively correlated with each other (r = 0.494, P < .01). Based on the ROC curve analysis, both Δ%T/NTmax (area under the curve [AUC] = .772, P < .01) and Δ%SUVmax (AUC = .829, P < .01) predicted good histologic response. However, there was no significant difference between the AUCs of Δ%T/NTmax and Δ%SUVmax (P = .44). The sensitivity and specificity for predicting good histologic response were 83.3% and 75.0%, for the criterion Δ%T/NTmax <–12.5%, and 80.0% and 81.3% for the criterion Δ%SUVmax <−49.0%, respectively.

The 99mTc-MDP bone scan and 18F-FDG PET scan are non-inferior to each other in predicting the histologic response of osteosarcoma treatments. The 99mTc-MDP bone scan and 18F-FDG PET scan showed respective advantages with differing features. Therefore, physicians should consider which scan is appropriate for their own institute based on the advantages of each scan and the circumstances of the institute.

Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography, 99mTc-methyl diphosphonate bone scintigraphy, histologic response, neoadjuvant chemotherapy, osteosarcoma

1. Introduction

Osteosarcoma is not a common malignancy.[1] In the United States, <1% of patients who are newly diagnosed with cancer each year are diagnosed with osteosarcoma.[1] However, it is the most common malignant osseous tumor in children.[1] Before the 1980s, the survival rate of patients with osteosarcoma was about 20% in the United States.[1,2] Even when the primary tumor was controlled, about 80% of patients did not survive due to metastasis. Since then, the survival rate has dramatically improved through the use of chemotherapy.[3] Chemotherapy is therefore currently established as a standard part of osteosarcoma treatment.[4]

For the treatment of osteosarcoma, neoadjuvant chemotherapy (NAC), surgical resection of the primary tumor and adjuvant chemotherapy are included in the current strategy.[5] Furthermore, it has been reported that the histologic response to preoperative chemotherapy is one of the most important prognostic factors for predicting survival.[5,6] However, tumor necrosis, as an indicator of histologic response, is typically checked with the resected specimen after surgery. It is difficult to differentiate the histologic responder or non-responder with NAC prior to surgery. If information about histologic response could be obtained before resection, it would be helpful in making treatment decisions for patients in advance. Therefore, non-invasive imaging methods have been extensively studied for checking histologic response.[7–11] Among them, 99mTc-methyl diphosphonate (99mTc-MDP) bone scan and 18F-fluorodeoxyglucose (FDG) for positron emission tomography/computed tomography (PET/CT) have been used to evaluate the histologic response after treatment. However, to date, there has been no study that directly compared 99mTc-MDP bone scan and 18F-FDG PET for predicting histologic response.

In this study, we compared directly the parameters of 99mTc-MDP bone scan and 18F-FDG PET for predicting histologic response of NAC in the same cohort of the patients with osteosarcoma.

2. Methods

2.1. Patients

A total 62 patients with osteosarcoma were retrospectively reviewed between September 2006 and December 2012. All the patients were treated with NAC and complete resection of the primary tumor. Surgical resection was performed between 6 and 10 weeks after completion of the NAC. 99mTc-MDP bone scan and 18F-FDG PET were performed before and after NAC. The initial scans were obtained within 2 weeks of NAC. The follow up scans after chemotherapy were obtained within 2 weeks prior to surgery. Magnetic resonance imaging (MRI) for evaluating the size of the primary tumor was performed within 2 weeks before NAC.

Our current study analyzed a total of 62 cases, including 21 of 26 cases that had been analyzed in our previous report[10] along with 41 new cases.

All patients underwent 2 cycles of NAC with high-dose methotrexate, adriamycin, and cisplatin according to the modified T10 protocol.[10,12] The protocol was described in detail in a previous report.[10] Surgical resection of the primary tumor was performed after completion of NAC. A surgical specimen was used for assessing histologic response according to the previous report.[10,13] A tumor with ≥90% necrosis was considered a good response.[13]

The study design was approved by the Review Board of our institution (IRB No.: K-1712-002-031), and written informed consents were exempted by the IRB. All procedures were performed in accordance with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

2.2. Image acquisition

2.2.1. 99mTc-MDP bone scan

A whole body bone scan (anterior and posterior images) was performed 3 hours after intravenous injection of 740 to 925 MBq of 99mTc-MDP using SymbiaT (Siemens Medical Solutions, Malvern, PA). A low energy, high resolution parallel collimator was used. The photopeak was centered at 140 keV and the matrix size was 256 × 1024.

2.2.2. 18F-FDG PET/CT

The 18F-FDG PET/CT scan was performed as described in the previous report.[10] Patients were intravenously injected with 18F-FDG (8.14 MBq/kg) after fasting for a minimum of 6 hours and blood glucose level did not exceed 7.2 mmol/L. The PET images were acquired 1 hour after injection using a PET/CT scanner (Biograph6; Siemens Medical Solutions, Malvern, PA). The CT images were obtained for attenuation correction immediately before the acquisition of PET images (130 kVp, 30 mA, 0.6 s/CT rotation, and a pitch of 6). The images were reconstructed with the ordered subsets expectation maximization algorithm (iteration 2, subset 8).

2.2.3. MRI

MR images were obtained with a 3.0-T MRI scanner (MAGNETOM Trio A Tim; Siemens Medical Solutions, Erlangen, Germany). T1-weighted sequence images with or without gadolinium enhancement and T2-weighted sequence without fat suppression images were obtained from all patients. Gadodiamide (Omniscan; GE Healthcare) was injected intravenously. On coronal sections of nonenhanced T1-weighted images, tumor lengths were evaluated, and on axial sections of enhanced T1-weighted sequence without fat suppression, the widths and depths of the tumors were measured.[10]

2.3. Image analysis

For the bone scan, the maximum pixel counts of the primary tumor (anterior image, TAmax; posterior image, TPmax) were obtained by manually drawing the region of interest (ROI), including the lesion with increased uptake compared with adjacent normal bone. To obtain the reference values, the same sized ROI was manually drawn in the contra-lateral area. With this contra-lateral ROI, the maximum pixel counts of the nontumor area (anterior images, NTAmax; posterior images, NTPmax) were acquired. The geometric mean count (GMC) was calculated for tumor or nontumor regions using the following equation[14]: 

2.3.

The tumor to nontumor ratio (T/NTmax) was calculated as GMC_tumor divided by GMC_non-tumor. T/NTmax before the chemotherapy was defined as T/NTmax1. T/NTmax after the chemotherapy was defined as T/NTmax2. The percentage change in T/NTmax (Δ%T/NTmax) between T/NTmax1 and T/NTmax2 was calculated using the following formula: Δ%T/NTmax = (T/NTmax2 – T/NTmax1)/T/NTmax1 × 100.

For the 18F-FDG PET scan, the maximum SUV value (SUVmax) of the primary tumor was acquired by manually drawing the volume of interest (VOI). The pre-chemotherapy SUVmax was defined as SUVmax1 and the post-chemotherapy SUVmax was defined as SUVmax2. The percentage change in SUVmax (Δ%SUVmax) between SUVmax1 and SUVmax2 was calculated using the following formula: Δ%SUVmax = (SUVmax2 – SUVmax1)/SUVmax1 × 100.

Tumor volume was defined at the initial MRI prior to the NAC as following the ellipsoid formula: 0.53 × tumor length × tumor width × tumor depth.[10]

2.4. Statistics

To predict histologic response, the receiver operating characteristic (ROC) curve analyses were performed using the parameters from the 99mTc-MDP bone scan and 18F-FDG PET scan. The areas under the curve (AUCs) for each parameter were calculated and the optimal cut-off values of each parameter for prediction of the histologic response were obtained based on the Youden index. Spearman rank correlation analysis was performed to compare the parameters between the 99mTc-MDP bone scan and 18F-FDG PET scan. To evaluate the influence of the clinical features on the histologic response, logistic regression analyses were performed. P values <.05 were regarded as statistically significant. Statistical analyses were performed using commercial software (Medcalc version 16.4.3, Medcalc software, Ostend, Belgium).

3. Results

3.1. Patient characteristics

Detailed clinical features are described in Table 1. After completion of NAC and surgical resection, good histologic response occurred in 30 patients. The other 32 patients showed poor histologic response.

Table 1.

Patient characteristics.

3.1.

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3.2. ROC curve analysis

In the ROC curve analysis of histologic response using 18F-FDG PET parameters, the AUC for Δ%SUVmax had the largest value (0.829) compared with other parameters (Fig. 1A). The ROC curve of Δ%SUVmax was significantly different from that of SUVmax1 (P < .01), whereas the ROC curve of Δ%SUVmax was not dissimilar from that of SUVmax2 (P = .80). In the ROC curve analysis using 99mTc-MDP bone scan, Δ%T/NTmax showed the largest value of the AUC (0.772) (Fig. 1B). The ROC curve of Δ%T/NTmax was not significantly different from the curves of T/NTmax1 and T/NTmax2 (P = .12 and P = .97, respectively). Based on the ROC curve analysis, Δ%SUVmax and Δ%T/NTmax were selected as representative parameters of 18F-FDG PET and 99mTc-MDP bone scan for further analysis.

Figure 1.

Figure 1

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ROC curve analysis between the histologic response and each parameter of the 18F-FDG PET and 99mTc-MDP bone scans. In ROC curves using the 18F-FDG PET parameters (A), Δ%SUVmax shows the largest AUC value (0.829). The AUC values for SUVmax1 and SUVmax2 are 0.571 and 0.817, respectively. In ROC curves using 99mTc-MDP bone scan parameters (B), the AUC for Δ%T/NTmax has the largest value (0.772). The AUC values for T/NTmax1 and T/NTmax2 are 0.601 and 0.770, respectively. The ROC curves regarding Δ%SUVmax and Δ%T/NTmax are compared (C). Two curves did not show significant difference (P = 0.44). 18F-FDG PET = 18F-Fluorodeoxyglucose positron emission tomography, 99mTc-MDP = 99mTc-methyl diphosphonate, Δ%SUVmax = percent changes of the maximum standardized uptake value, Δ%T/NTmax = percent changes of the maximum tumor-to-nontumor ratio, AUC = area under the curve, ROC = receiver operating characteristic.

The optimal cut-off values of Δ%SUVmax and Δ%T/NTmax for histologic response after NAC were calculated as –49.0% and –12.5%, respectively. Table 2 shows the sensitivity and specificity for predicting histologic response using the optimal cut-off values of Δ%SUVmax and Δ%T/NTmax. Both parameters could predict histologic response with high sensitivity and specificity. In addition, the ROC curves using these parameters did not show a statistically significant difference (P = .44) (Fig. 1C).

Table 2.

Predictive values of pretreatment 99mTc-MDP bone scan and 18F-FDG PET for the histologic response.

3.2.

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3.3. Correlation of parameters between 99mTc-MDP bone scan and 18F-FDG PET

A moderate positive linear correlation between Δ%SUVmax and Δ%T/NTmax was observed in the scatter plot (P < .01, rho = .494) (Fig. 2). The mean values of Δ%SUVmax and Δ%T/NTmax were –36.8 and 13.4, respectively (P < .01).

Figure 2.

Figure 2

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The correlation between Δ%SUVmax and Δ%T/NTmax. A moderate positive correlation exists between the 2 parameters (P < .01, rho = .494). Δ%SUVmax = percent changes of the maximum standardized uptake value, Δ%T/NTmax = percent changes of the maximum tumor-to-nontumor ratio.

3.4. Prognostic values for histologic response

The various clinical features including age, sex, American Joint Committee on Cancer (AJCC) stage, tumor volume based on MRI images, location of the primary tumor, and pathologic type were not statistically significant factors for histologic response based on the univariate logistic regression analyses. However, Δ%SUVmax and Δ%T/NTmax were significant prognostic factors for histologic response based on univariate (both P < .01) and multivariate logistic regression analyses (both P < .01) (Table 3).

Table 3.

Parameters related with histologic response after neoadjuvant chemotherapy in the univariate and multivariate analyses.

3.4.

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Representative images of good and poor histologic response are shown in Figs. 3 and 4.

Figure 3.

Figure 3

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A 17-year-old male patient underwent neoadjuvant chemotherapy due to osteosarcoma at the right distal femur. The 18F-FDG PET images before chemotherapy (A) and after chemotherapy (B) are shown as maximum intensity projections. The sagittal fused 18F-FDG PET images before chemotherapy (E) and after chemotherapy (F) are shown. SUVmax1 of the tumor (white arrow) is 9.4 and SUVmax2 of the tumor after chemotherapy (black arrow) is 3.7. The value of Δ%SUVmax is –60.9%. The bone scan images before chemotherapy (C) and after chemotherapy (D) are shown. T/NTmax1 of initial primary tumor is 15.2 (white arrowhead) and T/NTmax2 of tumor after chemotherapy is 4.2 (black arrowhead). Δ%T/NTmax is –72.1%. After surgical resection of the tumor, 95.0% necrosis was observed, which indicated good histologic response with neoadjuvant chemotherapy. SUVmax1 = prechemotherapy maximum standardized uptake value, SUVmax2 = postchemotherapy SUVmax, T/NTmax1 = maximum tumor-to-nontumor ratio before the chemotherapy, T/NTmax2 = T/NTmax after the chemotherapy, Δ%SUVmax = percent changes of the SUVmax, Δ%T/NTmax = percent changes of T/NTmax.

Figure 4.

Figure 4

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A 34-year-old male patient with osteosarcoma at right proximal tibia who underwent neoadjuvant chemotherapy. The 18F-FDG PET images before chemotherapy (A) and after chemotherapy (B) are shown as a maximum intensity projection. The axial fused 18F-FDG PET images before chemotherapy (E) and after chemotherapy (F) are shown. SUVmax1 of the tumor (white arrow) is 4.7 and SUVmax2 of the tumor after chemotherapy (black arrow) is 8.2. The value of Δ%SUVmax is 73.8%. The bone scan images before chemotherapy (C) and after chemotherapy (D) are shown. T/NTmax1 of initial primary tumor is 2.5 (white arrowhead) and T/NTmax2 of tumor after chemotherapy is 27.1 (black arrowhead). Δ%T/NTmax is 983.6%. After surgical resection of the tumor, 5.0% necrosis was observed, which indicated poor histologic response with neoadjuvant chemotherapy. SUVmax1 = prechemotherapy maximum standardized uptake value, SUVmax2 = postchemotherapy SUVmax, T/NTmax1 = maximum tumor-to-nontumor ratio before the chemotherapy, T/NTmax2 = T/NTmax after the chemotherapy, Δ%SUVmax = percent changes of the SUVmax, Δ%T/NTmax = percent changes of T/NTmax.

4. Discussion

In this study, we evaluated the histologic response in patients with osteosarcoma after completion of NAC using 99mTc-MDP bone scintigraphy and 18F-FDG PET/CT. The percentage change in SUVmax of the 18F-FDG PET scan and the percentage change in tumor to nontumor ratio in the 99mTc-MDP bone scan significantly predicted the histologic response of preoperative chemotherapy in patients with osteosarcoma. To the best of our knowledge, this is the first attempt to directly compare 99mTc-MDP bone scintigraphy and 18F-FDG PET/CT for predicting treatment response.

It was reported that many parameters of 18F-FDG PET/CT are correlated with the histologic response after NAC in the patients with osteosarcoma. For instance, in our previous studies, Δ%SUVmax, metabolic tumor volume (MTV) before NAC, and SUVmax after NAC are associated with histologic response.[10,15] Im et al[16] reported that SUVmax, peak SUV (SUVpeak), MTV, and total lesion glycolysis (TLG) during and after NAC are correlated with histologic response. It was reconfirmed through the current study that, Δ%SUVmax, the representative parameter, is correlated with the histologic response after NAC.

Bone scan using 99mTc-MDP is a sensitive tool for detecting primary bone tumor and bone metastasis,[8] but it has limitations in reflecting the treatment response in a relatively short time.[17] While 18F-FDG PET directly reflects the metabolism of viable cells, the 99mTc-MDP uptake on bone scan is based on blood flow and ion exchange, meaning that the bone scan reflects indirect osteoblastic activity rather than direct detection of viable tumors.[8] Despite such weakness of the bone scan, it was reported that the changes in tumor-to-background ratio (TBR) on bone scan before and after NAC in patients with osteosarcoma is associated with histologic response.[8] Such is consistent with our results. In the current study, Δ%T/NTmax on the 99mTc-MDP bone scan predicted the histologic response after NAC.

Δ%T/NTmax on 99mTc-MDP bone scan and Δ%SUVmax on 18F-FDG PET showed positive correlation with statistical significance. Similarly, Franzius et al[18] reported that tumor to nontumor ratios on 18F-FDG PET scans before NAC show a significant positive correlation with tumor to nontumor ratios on 99mTc-MDP bone scintigraphy before NAC. When comparing the AUC curves for Δ%SUVmax on the 18F-FDG PET scan and Δ%T/NTmax on the 99mTc-MDP bone scan for prediction of histologic response, the AUC values of the 2 parameters were not statistically different. This suggests that both modalities are non-inferior to each other in predicting histologic response. Furthermore, multivariate analyses showed that both parameters are independent prognostic factors for histologic response. Clinical data other than the parameters of 99mTc-MDP bone scan and 18F-FDG PET showed no significant correlation with histologic response. Notably, the tumor volume at initial diagnosis, known as an important independent prognostic factor for metastasis-free survival,[12] did not show any significant correlation with histologic response. This result is consistent with that of a previous report.[19]

However, in our results, the differences between the values before and after treatment were much greater in Δ%SUVmax than in Δ%T/NTmax. Furthermore, although there is no significant difference, the AUC value of Δ%SUVmax was slightly greater than that of Δ%T/NTmax. This suggests that the change from before and after NAC can be more easily detected on the 18F-FDG PET scan than on the 99mTc-MDP bone scan. This may be the result of differences in imaging modalities. The PET/CT image is tomographic while the bone scan is planar. Therefore, PET/CT provides higher resolution images with higher sensitivity and specificity in lesion detection compared with conventional planar bone scans.[20] It is not easy to directly compare PET, a tomographic image, with the bone scan, a planar image. The sensitivity of bone scan for lesion detection is reported to be 70% to 90%.[21] However, SPECT, a tomographic image, can increase the sensitivity for lesion detection to 95%.[21] In this study, SPECT images were not included because it is not a routinely performed test and this study is a retrospective study. When bone SPECT can be performed to evaluate the treatment response of the primary tumor, lesions can be evaluated with higher sensitivity and higher resolution when compared with the bone scan. Superior resolution of SPECT over the bone scan can provide better ability to differentiate the lesion in the bone versus soft tissue area.

Another weakness of the bone scan compared with PET is the method used to quantify the uptakes. In the current study, semi-quantitative methods were adapted. However, the tools for direct measurement of SUVs have been developed in SPECT, which can solve the quantification problem.[22] It will be essential to compare quantitative results from SPECT and PET for further clarification of this study. Furthermore, it will also be necessary to compare 18F-FDG PET with 18F-NaF PET, a novel PET tracer, which exhibits higher sensitivity than bone scans and bone SPECT.

To date, there have been several studies that compared FDG PET/CT and bone scans in osteosarcoma patients, mainly focusing on metastasis. It was reported that 18F-FDG PET/CT not only displays more sensitivity in detecting bone metastasis than the 99mTc-MDP bone scan in the diagnosis of osteosarcoma,[15,23] but also predicts overall and event-free survival of osteosarcoma patients.[18] In addition to the different level of information that may be acquired by PET/CT and a bone scan, another feature of PET/CT is patient convenience. Because the 18F-FDG PET scan is performed <2 hours after the injection of 18F-FDG, the total time required is much less than that for a 99mTc-MDP bone scan. On the other hand, some advantages of the 99mTc-MDP bone scan are its cost-effectiveness[24] and low radiation exposure. The effective dose of a bone scan for an adult is approximately 3 to 4 mSv,[25] whereas the effective dose of a 18F-FDG PET/CT whole body scan using 10 mCi of 18F-FDG is about 7 mSv with additional radiation exposure by CT.[26] Bone scans may reduce cost and total radiation exposure when compared with PET/CT.

There are some limitations to our study. First, the scanners for PET and bone scan can affect the uptake count of FDG and MDP. The estimated cut-off values for Δ%SUVmax on the PET scan and for Δ%T/NTmax on the bone scan may differ. Second, the flare phenomenon may be observed in the bone scan after treatment. It has been mostly observed in patients with breast and prostate cancer.[27] Although there is no report of specific incidence of flare after treatment of osteosarcoma, sufficient time interval after treatment to exclude the flare phenomenon would be needed. In this study, the time interval from the end of the treatment to the bone scan may have been relatively short. Sufficient consideration should be given to the possibility of a flare phenomenon when predicting therapeutic response using bone scans.

In conclusion, 18F-FDG PET/CT and 99mTc-MDP bone scintigraphy have been found to be non-inferior to each other in predicting the histologic response of treatments. Both scans had their own advantages although with differing features. Therefore, it is advised that physicians should consider which scan is appropriate for their institute based on the advantages and features of each scan and the circumstance of the institute. If PET/CT is not available, the 99mTc-MDP bone scan may be a non-invasive tool for predicting the histologic response to NAC in patients with osteosarcoma.

Author contributions

Conceptualization: Inki Lee, Byung Hyun Byun, Byung Il Kim, Chang-Bae Kong, Sang Moo Lim.

Data curation: Chang-Bae Kong, Jae-Soo Koh.

Formal analysis: Inki Lee, Byung Hyun Byun, Ilhan Lim.

Funding acquisition: Chang-Bae Kong, Sang Moo Lim.

Methodology: Won Seok Song, Wan Hyeong Cho, Jae-Soo Koh.

Resources: Won Seok Song, Wan Hyeong Cho.

Supervision: Ilhan Lim, Byung Il Kim, Chang-Bae Kong.

Validation: Inki Lee, Chang-Bae Kong.

Visualization: Inki Lee.

Writing – original draft: Inki Lee, Byung Hyun Byun, Sang Moo Lim.

Writing – review & editing: Inki Lee, Byung Hyun Byun, Chang-Bae Kong, Won Seok Song, Wan Hyeong Cho, Jae-Soo Koh, Sang Moo Lim.

Footnotes

Abbreviations: Δ%SUVmax = percent changes of the maximum standardized uptake value, Δ%T/NTmax = percent changes of the maximum tumor-to-nontumor ratio, 18F-FDG = 18F-fluorodeoxyglucose, 99mTc-MDP = 99mTc-methyl diphosphonate, NAC = neoadjuvant chemotherapy, PET/CT = positron emission tomography/computed tomography.

CBK and SML are co-corresponding authors.

This study was supported by a grant of the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by the Ministry of Science and ICT, Republic of Korea (50461–2017 and 50473–2017).

The authors have no conflict of interest.

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