1. 2011 ACRIN Annual Meeting ACRIN 6671/GOG 0233 REVIEW RESULTS ACRIN PI: M. ATRI GOG PI: M. GOLD FERUMOXTRAN-10 MRI REVIEW RESULTS ACRIN PI: M. ATRI GOG PI: M. GOLD Zhang Z, Marques H, Gorelick J, Harisinghani M, Sohaib A, Koh DM, Raman S, Gee M, Choi H, Landrum L, Manne R, Chuang L, Yu J, McCourt C

2. 2011 ACRIN Annual Meeting Ferumoxtran-10 nanoparticle, an ultra-small particle iron oxide (USPIO) agent improves sensitivity/specificity of MRI to detect metastatic lymphadenopathyFerumoxtran-10 nanoparticle, an ultra-small particle iron oxide (USPIO) agent improves sensitivity/specificity of MRI to detect metastatic lymphadenopathy Harisinghani et al. showed a per patient sensitivity/specificity of 100%/96% for LN detection in 80 prostate cancer patientsHarisinghani et al. showed a per patient sensitivity/specificity of 100%/96% for LN detection in 80 prostate cancer patients Rockall et al. showed significantly higher sensitivity than size criteria without compromise of specificity in 44 endometrial and cervical cancer patientsRockall et al. showed significantly higher sensitivity than size criteria without compromise of specificity in 44 endometrial and cervical cancer patients INTRODUCTION

3. 2011 ACRIN Annual Meeting To determine efficacy of f-10 in the evaluation of LN metastasis from loco-regionally advanced cervical cancer OBJECTIVE

4. 2011 ACRIN Annual Meeting STUDY DESIGN Loco-regionally advanced CALoco-regionally advanced CA Pre-operative MRI 24-36hrs post f-10Pre-operative MRI 24-36hrs post f-10 Extra-peritoneal/laparoscopic abdominal & pelvic lymph node samplingExtra-peritoneal/laparoscopic abdominal & pelvic lymph node sampling Per region comparison of lymphadenectomy and f-10 MRI for 8 regions:Per region comparison of lymphadenectomy and f-10 MRI for 8 regions: Rt. & Lt. para-aorticRt. & Lt. para-aortic Rt. & Lt. common iliacRt. & Lt. common iliac Rt. & Lt. external iliacRt. & Lt. external iliac Rt. & Lt. obturatorRt. & Lt. obturator ABDOMEN PELVIS

5. 2011 ACRIN Annual Meeting STUDY POPULATION 33 women 30 – 67 year (mean 49 ±11) Primary tumor: 5.4 cm ±1.5 cm Disease Stage: IB2:12, IIA:3, IIB:15, IIIB:3 Pathology: Squamous cell;29, Adenoca;3, Rhabdomyosarcoma;1 Grade: 1 (1), grade 2 (20), grade 3 (12)

6. 2011 ACRIN Annual Meeting 1.5 Tesla MRI, pelvic phased array coil1.5 Tesla MRI, pelvic phased array coil Coverage from IMA origin to symphysis pubisCoverage from IMA origin to symphysis pubis 2.6 mg/kg of f-10 diluted in 100 ML of normal saline (IND agent, IND held by NCI) (provided by AMAG Inc.)2.6 mg/kg of f-10 diluted in 100 ML of normal saline (IND agent, IND held by NCI) (provided by AMAG Inc.) Infused over 30 minutesInfused over 30 minutes T1W, T2W, and T2*GRE sequencesT1W, T2W, and T2*GRE sequences MRI EXAMINATION

7. 2011 ACRIN Annual Meeting Independent review by seven readers 1st Review: All sequences excluding T2* GRE sequence Lymph node positive:Lymph node positive: short axis > 8mm for a node with short axis > half of longshort axis > 8mm for a node with short axis > half of long short axis > 10mm for a node with short axis 10mm for a node with short axis < half of long 2nd. Review: All sequences including T2* GRE sequence Lymph node positive:Lymph node positive: High signal LN or high signal foci within LN MRI REVIEW PROCESS

8. 2011 ACRIN Annual Meeting Institutional pathology review Presence/absence of LN metastasis, size of the largest focus of metastasis/region, size of the largest positive LN/region recorded PATHOLOGY REVIEW

9. 2011 ACRIN Annual Meeting Degree of suspicion of LN metastasis recorded on a 6 point scale Test result dichotomized to positive/negative using top or bottom 3 scores to calculate sensitivity/specificity Abdomen or pelvis positive if one or more region was positive in abdomen or pelvis on the same side on MRI and surgery STATISTICAL ANALYSIS

10. 2011 ACRIN Annual Meeting Prevalence of LN metastasis Abdomen: 36% (12/33)Prevalence of LN metastasis Abdomen: 36% (12/33) Pelvis: 64% (21/33) Pelvis: 64% (21/33) Median size of the largest focus of cancer 18mm (range 2–50mm)Median size of the largest focus of cancer 18mm (range 2–50mm) Mean size of the largest focus Abdomen (13.7mm) Pelvis (18.8mm) P value (0.018)Mean size of the largest focus Abdomen (13.7mm) Pelvis (18.8mm) P value (0.018) RESULTS

11. 2011 ACRIN Annual Meeting RESULTS MRI Accuracy Values T2* Insensitive Sequences All Sequences P Value RangeAverageRangeAverage P E L V I S Sensitivity0.76-0.810.78 (0.70-0.84)0.71-0.900.83 (0.76-0.88)0.243 Specificity0.56-0.890.75 (0.62-0.84)0.22-0.670.48 (0.35-0.61) 0.003 NPV0.50-0.640.59 (0.48-0.69)0.25-0.670.55 (0.41-0.67)0.629 PPV0.80-1.000.88 (0.81-0.92)0.68-0.850.79 (0.72-0.84) 0.049 Accuracy0.70-0.800.77 (0.70-0.82)0.57-0.770.72 (0.66-0.78)0.315 ABDOMENABDOMEN Sensitivity0.50-0.580.54 (0.43-0.64)0.50-0.750.60 (0.49-0.70)0.438 Specificity0.68-0.890.83 (0.75-0.88)0.58-0.890.75 (0.67-0.82)0.136 NPV0.70-0.760.74 (0.66-0.80)0.69-0.830.75 (0.67-0.81)0.878 PPV0.54-0.750.66 (0.54-0.76)0.47-0.750.60 (0.49-0.70)0.454 Accuracy0.65-0.740.71 (0.65-0.77)0.58-0.770.69 (0.63-0.75 )0.600

12. 2011 ACRIN Annual Meeting RESULTS MRI Accuracy Values T2* Insensitive Sequences All Sequences P Value RangeAverageRangeAverage P E L V I S Sensitivity0.76-0.810.78 (0.70-0.84)0.71-0.900.83 (0.76-0.88)0.243 Specificity0.56-0.890.75 (0.62-0.84)0.22-0.670.48 (0.35-0.61) 0.003 NPV0.50-0.640.59 (0.48-0.69)0.25-0.670.55 (0.41-0.67)0.629 PPV0.80-1.000.88 (0.81-0.92)0.68-0.850.79 (0.72-0.84) 0.049 Accuracy0.70-0.800.77 (0.70-0.82)0.57-0.770.72 (0.66-0.78)0.315 ABDOMENABDOMEN Sensitivity0.50-0.580.54 (0.43-0.64)0.50-0.750.60 (0.49-0.70)0.438 Specificity0.68-0.890.83 (0.75-0.88)0.58-0.890.75 (0.67-0.82)0.136 NPV0.70-0.760.74 (0.66-0.80)0.69-0.830.75 (0.67-0.81)0.878 PPV0.54-0.750.66 (0.54-0.76)0.47-0.750.60 (0.49-0.70)0.454 Accuracy0.65-0.740.71 (0.65-0.77)0.58-0.770.69 (0.63-0.75 )0.600

13. 2011 ACRIN Annual Meeting MRI Accuracy Values T2* Insensitive Sequences All Sequences P Value RangeAverageRangeAverage COMBINEDCOMBINED Sensitivity0.78-0.830.80 (0.73-0.85)0.78-0.960.86 (0.79-0.90)0.144 Specificity0.63-0.880.73 (0.60-0.83)0.25-0.630.43 (0.30-0.56) 0.002 NPV0.50-0.600.55 (0.44-0.66)0.29-0.670.51 (0.37-0.65)0.642 PPV0.86-0.950.90 (0.83-0.94)0.75-0.870.81 (0.75-0.86) 0.043 Accuracy0.74-0.810.78 (0.72-0.83)0.65-0.810.75 (0.68-0.80)0.430 RESULTS

14. 2011 ACRIN Annual Meeting INTER-OBSERVER AGREEMENT Comparison of All Readers T2* Insensitive Sequences All Sequences KappaP ValueKappaP Value Abdomen 0.74< 0.00010.54< 0.0001 Pelvis 0.84< 0.00010.52< 0.0001 Combined 0.89< 0.00010.46< 0.0001

15. 2011 ACRIN Annual Meeting T2W T2*

16. 2011 ACRIN Annual Meeting T2W T2*

17. 2011 ACRIN Annual Meeting T2 * T2W

18. 2011 ACRIN Annual Meeting Results of this study suggests higher sensitivity of ferumoxtran-10 MRI over standard MRI that did not reach statistical significanceResults of this study suggests higher sensitivity of ferumoxtran-10 MRI over standard MRI that did not reach statistical significance Specificity of ferumoxtran-10 MRI was significantly lower than standard MRISpecificity of ferumoxtran-10 MRI was significantly lower than standard MRI Lower specificity may be due to issues related to mismatching of metastatic LNs on MRI and surgery and lack of removal of involved LNsLower specificity may be due to issues related to mismatching of metastatic LNs on MRI and surgery and lack of removal of involved LNs SUMMARY