Introduction

Ewing Sarcoma Family of Tumors (ESFT) is the second most common primary malignant bone tumor in children and young adults next to osteosarcoma¹. ESFT is treated with systemic neoadjuvant chemotherapy for local control. The assessment of chemotherapy response is done by the RECIST 1.1 criteria² (Response evaluation criteria in solid tumors) after completion of chemotherapy or by histopathology of resected tumor. However, early noninvasive assessment of tumor response to chemotherapy may help to prevent the non-responders from undergoing ineffective chemotherapy regimen and can be directed to alternate therapeutic option. Therefore, this study was undertaken to assess the role of diffusion weighted (DW) MRI in the early evaluation of chemotherapy response in ESFT using correlation with RECIST 1.1.

Methods

Patients: Sixteen patients (n=16; age=16.8±5.6years; Male:Female=10:6) with biopsy proven ESFT were analysed prospectively. All patients underwent neoadjuvant chemotherapy: VAC (Vincristine, Doxorubicin/Actinomycin-D, Cyclophosphamide) alternated with IE (Ifosfamide, Etoposide) for 5 complete cycles at three weeks interval followed by surgery and/or chemotherapy/chemo-radiotherapy.
MRI acquisition: Conventional T1W and T2W along with DW-MRI scan was acquired on a 1.5Tesla scanner (Achieva; Philips,Netherlands) at three time points: first, within 7 days prior to starting chemotherapy (baseline); second, after one week of 1^st chemotherapy cycle (early-time-point) and third, after completion of chemotherapy (last-time-point). DW-MRI sequence was acquired using free breathing SE-EPI(Spin-echo Echo Planar Imaging) using parallel imaging at b-values of 0,100,500,1000 s/mm² and diffusion sensing gradients were applied in all three orthogonal planes. ADC maps were derived from all b-values automatically on a voxel-by-voxel basis.
RECIST 1.1 for chemotherapy response: RECIST 1.1 criteria² was considered as the clinical standard for evaluation of response to chemotherapy. Complete Response(CR) was total disappearance of all target lesions; Partial Response(PR) was minimum 30% decrease in the sum of diameters of target lesions with reference to baseline; Progressive Disease(PD) was minimum 20% increase and an absolute increase of at least 5mm in the sum of diameters of target lesions; Stable Disease(SD) was if neither PR and nor PD. Patients with PR and CR were categorized as responders and SD and PD were categorized as non-responders.
Quantitative image analysis: The largest diameter of tumor was measured manually on axial T2W images at baseline(S_B), early-time-point(S_E) and last-time-point(S_L). Percentage size changes between baseline and early-time-point(Δ%S_E) and between baseline and last-time-point(Δ%S_L) were calculated.
Region of interest(ROI) of the largest tumor cross-section was drawn manually on axial DWI (b=1000s/mm²) slice and automatically transferred to the ADC map with reference to T2W images. Absolute mean ADC in tumor ROI and normalized ADC (nADC) by obtaining ratio of ADC in tumor and muscle^3,4, were calculated. Muscle ADC was calculated by placing 10 mm² size ROI on adjacent healthy skeletal muscle. ADC and nADC values were calculated for baseline (ADC_B, nADC_B) and early-time-point (ADC_E, nADC_E). At early-time-point with respect to baseline values, absolute change in ADC (ΔADC_E) and nADC (ΔnADC_E) and percentage change in ADC (Δ%ADC_E) and nADC (Δ%nADC_E) were calculated.
Statistical analysis: Baseline parameters and change in the parameters after one cycle of chemotherapy were assessed for early detection of chemotherapy response. Inter-group comparison between responders and non-responders was performed using Mann-Whitney-Wilcoxon test. Intra-group comparison between baseline and early-time-point was performed using Wilcoxon-signed-rank test. Receiver-operating-characteristics (ROC) curve analysis was used to assess the predictability of chemotherapy response by quantitative parameters. Data was analysed by using SPSS v15 and a p-value=0.05 was considered for statistical significance.

Results

Based on RECIST1.1 score, responder:non-responder was 10(CR:2,PR:8):6(SD:5,PD:1). Among responders and non-responders, S_B, Δ%S_E, and Δ%S_L are presented in Table1. Δ%S_E in responders (26±14%) was significantly higher (p=0.001) compared with non-responders (4.6±10%).
At baseline ADC_B, nADC_B and its changes at early-time-point are presented in Table2. At baseline, comparatively lower mean ADC_B ((0.811±0.262 vs. 0.977±0.246)×10^-3mm²/sec; p=0.360) and significantly lower mean nADC_B ((0.710±0.299 vs. 0.925±0.262)×10^-3mm²/sec; p=0.035) were observed among responders than the non-responders. At early-time-point, significantly higher Δ%nADC_E among responders was noted (75%±42%; p<0.001) than the non-responders (48%±67%; p=0.086).
ROC curve analysis of size and diffusion parameters are presented in Table3. nADC_B produced AUC=0.7 for predicting chemotherapy response at baseline. At early-time-point for predicting chemotherapy response, ∆ADC_E,∆%ADC_E produced AUC=0.701,0.720 respectively; while ∆nADC_E, ∆%nADC_E produced AUC=0.710,0.750 respectively and ∆%S_E produced the highest AUC=0.938 (optimal-cutoff≥13%,sensitivity=83%,specificity=100%) for predicting chemotherapy response.
DWI b=1000s/mm² and corresponding ADC map of a representative patient each from the responder and non-responder group are presented in Figure1 and Figure2 respectively.

Discussion

In this study higher pre-treatment ADC values in tumor have been observed among non-responders indicating possible necrosis in tumor and less sensitivity to cytotoxic agents due to decreased perfusion in tumor similar to earlier studies⁵. After chemotherapy significant increase in ADC was observed among responders as also reported by^6,7. The percentage change in nADC was a better predictor of response compared to absolute nADC change; because, for a small absolute change in ADC, the relative percentage change may be significant. The optimal timing for imaging to detect the rise in ADC is crucial and hard to predict and required further studies with large sample size.

Conclusion

Baseline nADC and its change after the first cycle of chemotherapy can be used as non-invasive surrogate markers of early assessment of response to chemotherapy in patients with ESFT.

Acknowledgements

No acknowledgement found.

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