Rationale and Objectives
Aim of the study was to compare between volumetric and unidimensional approaches for treatment response monitoring in a nude rat model of experimental bone metastases. For the volumetric approach, an automated segmentation algorithm of osteolytic lesions was introduced and compared to manual volumetry.
Material and Methods
Nude rats bearing osteolytic metastases were treated with zoledronate and sunitinib and compared to controls. Treatment response was assessed longitudinally in vivo using flat-panel volumetric computed tomography at days 30, 35, 45, and 55 after tumor cell inoculation. The mean sizes and volumes of osteolytic lesions were determined according to response evaluation criteria in solid tumors (RECIST) and by automated and manual volumetry (software: MITK [The Medical Imaging Interaction Toolkit, Heidelberg, Germany] and VIRTUOS, Heidelberg, Germany).
Results
In contrary to RECIST, the manual volumetric approach indicated a significant decrease in osteolytic lesion volume in response to treatment. The presented automatic segmentation algorithm for treatment monitoring identified bone metastases adequately and assessed changes in the osteolytic lesion volume over time according to manual volumetry.
Conclusions
In an animal model, volumetric treatment response assessment of osteolytic bone metastases is superior to unidimensional measurements, and automated volumetric segmentation may be a valuable alternative to manual volume determination.
Bone is the most common site of metastasis for breast and prostate cancer. Bone pain, pathologic fractures, and immobility are clinical complications of bone metastasis which can profoundly impair quality of life for long-term survivors . Treatment options for inhibiting breast cancer bone metastases are currently including the systemic treatment options bisphosphonates, chemotherapy, and hormone therapy. Furthermore, novel therapeutic approaches for metastatic breast cancer enclose antiangiogenic treatments .
Treatment response assessment of bone metastases is complicated because of the complex morphology of skeletal lesions and the slow turnover of bone matrix on therapy . Beside magnetic resonance imaging (MRI) for evaluation of bone marrow involvement of metastasis, computed tomography (CT) is commonly used in clinical practice to determine morphologic osseous changes after application of treatment. The commonly used classification system for therapy monitoring in solid tumors is the response evaluation criteria in solid tumors (RECIST) that is based on unidimensional measurement of primary tumors and metastases as determined by the largest lesion diameter . Bone metastases, however, have been considered as “immeasurable” in the initial version of these guidelines because of the complex morphology . In the revised RECIST guidelines (version 1.1), some additions have been made defining osteolytic or mixed lesions with identifiable soft tissue masses as measurable lesions by CT and MRI . Thus, measuring unidimensional diameters of the soft tissue component of skeletal metastases is the current standard for response evaluation.
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Material and methods
Animal Model and Treatment
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Imaging Technique
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Imaging Data Analysis
Response evaluation criteria in solid tumors
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Manual volumetry
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Automated software tool for the analysis of osteolytic lesions
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Statistical analysis
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Histologic Staining
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Results
Therapy Response
RECIST (Manual Measurement Unidimensional)
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Table 1
Study Results
Day 30 Day 35 Day 45 Day 55 RECIST (cm) Control 0.29 ± 0.05 0.39 ± 0.07 0.50 ± 0.06 0.60 ± 0.09 Zoledronate 0.40 ± 0.06 0.42 ± 0.05 0.37 ± 0.07 0.41 ± 0.06 Sunitinib 0.37 ± 0.07 0.42 ± 0.04 0.44 ± 0.05 0.41 ± 0.05 Manual (mL) Control 0.04 ± 0.01 0.05 ± 0.01 0.08 ± 0.02 0.12 ± 0.04 Zoledronate 0.04 ± 0.01 0.05 ± 0.02 0.06 ± 0.02 0.06 ± 0.02 Sunitinib 0.04 ± 0.01 0.04 ± 0.01 0.04 ± 0.01 0.03 ± 0.01** Automatic (mL) Control 0.09 ± 0.04 0.18 ± 0.05 0.27 ± 0.09 0.32 ± 0.1 Zoledronate 0.07 ± 0.03 0.24 ± 0.14 0.15 ± 0.07 0.17 ± 0.08 Sunitinib 0.05 ± 0.02 0.14 ± 0.04 0.23 ± 0.05 0.17 ± 0.05
For in vivo experiments, all mean values from day 30, 35, 45, and 55 are given in absolute numbers ± standard error. Numbers for manual volumetry were reported previously .
Asterisks denote a significant difference between groups (** P < .01).
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Manual volumetry
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Automated volumetry
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Histology
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Comparison Between Manual and Automated Segmentation
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Table 2
Comparison Between Manual and Automated Segmentation (Bland–Altman Analysis)
Volume Mean Manual Mean Automatic Mean Difference Deviation Factor Small 0.02 0.05 0.03 2.2 Medium 0.05 0.18 0.12 3.4 Large 0.12 0.31 0.21 2.7 Mean Value 0.06 0.17 0.36 2.8
The mean values for manual and automatic segmentation, as well as the mean difference and deviation factor for the techniques, are given for small (0.008–0.029 mL), medium (0.03–0.078 mL), and large (0.079–0.309 mL) bone Metastases.
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Discussion
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Acknowledgments
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