Esha Baidya Kayal1, Devasenathipathy Kandasamy2, Kedar Khare3, Sameer Bakhshi4, Raju Sharma2, and Amit Mehndiratta1,5
1Centre for Biomedical Engineering, Indian Institute of Technology, Delhi, New Delhi, India, 2Radio Diagnosis, All India Institute of Medical Sciences, New Delhi, New Delhi, India, 3Department of Physics, Indian Institute of Technology, Delhi, New Delhi, India, 4Department of Medical Oncology, Dr. B.R. Ambedkar Institute-Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences, New Delhi, New Delhi, India, 5Department of Biomedical engineering, All India Institute of Medical Sciences, New Delhi, New Delhi, India
Synopsis
Osteosarcoma
(OS) is the most common primary malignant bone tumor in children and adolescents. Monitoring treatment response
during chemotherapy might help in better and personalized therapeutic options
improving overall therapeutic outcome. RECIST1.1 is the standard imaging based
non-invasive treatment response evaluation criteria in solid tumors. Quantitative
Intravoxel incoherent motion (IVIM) parameters and their histogram analysis were
performed in Osteosarcoma in characterizing chemotherapy response with respect to RECIST1.1 criteria. IVIM parameters and its histogram analysis revealed
clinically useful information in characterizing chemotherapy response in
Osteosarcoma.
Purpose
Osteosarcoma
(OS) is the most common primary malignant bone tumor in children and adolescents1. Five-year disease-free survival rate for
localized OS is 60–70%, whereas disease free survival rate is less than 20% in
patients presenting with metastasis1. Monitoring
treatment response during chemotherapy might help in better and personalized
therapeutic options improving overall therapeutic outcome2–5. RECIST1.1 is the standard imaging based
non-invasive treatment response evaluation criteria in solid tumors6. Purpose was to investigate the quantitative
Intravoxel incoherent motion (IVIM)7 parameters and their histogram analysis in
characterizing chemotherapy response in Osteosarcoma with respect to RECIST1.1 criteria.Methods
IVIM dataset for twenty patients (n=30; Male:Female=22:8; Age=17.4±2.3years;
Metastatic:localized=18:12) with Osteosarcoma were acquired. All patients
underwent 3 cycles of neoadjuvant chemotherapy (NACT) at every 3 weeks. IVIM
dataset were acquired at three time-points – pre-NACT (t0), after 1stNACT
(t1) and after 3rdNACT (t2) using free breathing Spin Echo-Echo
Planar imaging with varying gradient strengths at 11 b-values
(0,10,20,30,40,50,80,100,200,800 sec/mm2).
Tumor volume (in cc) at different time-points was determined
separately using region of interest (ROI) drawn manually by an expert
radiologist across the tumor on each b=800sec/mm2
DWI image (DWI800) with reference to the morphological T1W and T2W
images at three time-points. Tumor-diameter (in cm) was measured at all three time-points using
demarcated ROI having the maximum cross-sectional area of tumor. Changes in
tumor-diameter across time were calculated and RECIST1.1 criteria6 was calculated as Complete-response (CR):
total disappearance of tumor; Partial-response (PR): Minimum 30% decrease in tumor-diameter; Progressive-disease (PD): minimum
20% and 5 mm absolute increase in tumor-diameter; Stable-disease (SD): neither
PR nor PD.
Apparent diffusion coefficient(ADC) and IVIM parameters such as Diffusion coefficient(D), Perfusion coefficient(D*), Perfusion fraction(f) were estimated in tumor volume at
different time-points (t0,t1&t2) using state-of –the art IVIM analysis
methodology, bi-exponential model with Total Variation(TV) penalty function
(BE+TV)8. It has been shown that BE+TV may
be more reliable for IVIM analysis compared to voxel-wise fitting of the IVIM
bi-exponential (BE) model8. Histogram analysis (mean,
standard-deviation, skewness, kurtosis, entropy) was performed on quantitative parameters
(ADC,D,D*&f) and compared with RECIST1.1 score. One-way ANOVA followed by Tukey post-hoc test was used to evaluate
statistical significance (p<0.05) in parameters between response
groups. Performance of significant parameters in identifying NACT response was
assessed using Receiver-operating-characteristic curve (ROC) analysis at
time-points t0 and t1. Quantitative parameters evaluation and histogram
analysis was performed using an in-house built toolbox in MATLAB® (MathWorks
Inc., v2017, Philadelphia, USA) and statistical analysis were performed using SPSS
16.0 software.Results
At t0, average
tumor-diameter and tumor-volume in patient cohort
were 9.48 ± 3.23 cm and 532.45 ± 518.77cc respectively and average ADC and D were observed as 1.39±0.3x10-3 mm2/s
& 1.3±0.3 x10-3 mm2/s respectively and average D* and f were observed as 28.44±10.34x10-3 mm2/s
& 13.95±2.83% respectively among all
patients. According to RECIST1.1 criteria, 8 (27%),
16 (53%) and 6 (20%) patients were categorized as partial-responder (PRs),
stable-disease (SD) and progressive-disease (PD) respectively. Tumor-diameter and tumor-volume significantly decreased in PR (~35%
& ~55%), increased (~16% % ~45%) among PD group (~16% % ~45%) and did not
change noticeably among SDs (~10% & ~4%) after chemotherapy. Average parameter values for different response groups at three
time-points are depicted in Table1. During NACT, ADC and D significantly (p<10-3) increased (~25-30%) in all response groups. D* significantly decreased (p=0.009) among
PRs after t1 and t2; while among SD group D*
significantly reduced only after t2 (p=0.001);
while among PDs it was almost stable (p>0.26). f showed decreasing trend (~12-17%
respectively) in PR and SD groups and were almost stable in PD group. Figure1, Figure 2 & Figure3 illustrate
parametric maps of representative patients each from PR, SD and PD group respectively at different time-points. According
to ANOVA test statistically significant histogram parameters at time-points t0,
t1 and t2 are represented in Table2. At time-point t1, variance of D* (p=0.02)
and skewness of f (p=0.03) and
at time-point t2, variance and entropy of D*
(p=0.003,0.001) and skewness and entropy of f (p=0.02,0.001) were significantly different among response
groups. D*-variance ((2.94 vs 4.45 and 6.87)x10-4), D*-entropy (7.45 vs
8.87 and 9.23), f-skewness (0.78 vs 1.23 and 1.1) and f-entropy (7.89 vs
9.21 ans 9.33) were lower among PRs than the SD and PD response groups after
completion of chemotherapy. At t1, using ROC analysis D*-variance and f-skewness jointly showed AUC = 0.79 in classifying PR group (sensitivity=74%;
specificity=72%) among all patients and AUC
= 0.75 in classifying SD group (sensitivity=77%; specificity=75%) from
rest of the patients.Discussion
Estimated ADC and D were in agreement with
each other and their values showed increasing trends and overlapping values
among different response groups during course of NACT were indication of
reduced cellularity in tumor as expected after NACT2-5. Decreased perfusion
parameters (D*, f) were observed among PR and SD groups that could be
indication of reduced angiogenesis and were almost stable in PD group.
Histogram parameters variance, entropy of D*
and f indicating heterogeneity in
angiogenesis pattern in tumor were also lower among PRs than that of SD and PD
groups.Conclusion
Quantitative
IVIM parameters evaluated using BE+TV method and their histogram analysis revealed clinically useful
information in characterizing chemotherapy response in Osteosarcoma and may be
benificial to explore further. Acknowledgements
No acknowledgement found.References
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