1. Mechanism of Action Combidex in MR Imaging Mukesh Harisinghani, MD Department of Radiology, Massachusetts General Hospital

2. 2 Overview Current limitations for LN staging in cancer Combidex enhanced MRI  Mechanism of action  Fulfills unmet clinical need of staging LN in patients with known primary cancer

3. 3 Why Image Lymph Nodes? Accurate staging of the primary cancer Appropriate treatment  Prostate Cancer  LN Positive  Treatment changed to non-surgical Get a sense of the prognosis  Bladder Cancer  Node Negative  10-year survival 57–87%  Node Positive  5-year survival 35–38% Risk of death increases 20% with each additional + LN Cheville et al. Cancer 97, 2003.

4. 4 Current LN Staging Non-Invasive  Imaging Invasive  Surgical LN Sampling (gold standard)

5. 5 Size Criteria < 10 mm < 8 mm Benign > 10 mm > 8 mm Malignant

6. Benign Malignant 18 mm in short axis5 mm in short axis Size criterion is inaccurate

7. Morphology – Fatty Hilum Malignant Benign

8. 8 Morphology – Central Necrosis CT in Cervical Cancer  Positive predictive value of 100% for nodal metastases  Most necrotic nodes had diameter > 2 cm Yang et al. AJR 2000;175.

9. 9 Pelvic Lymphadenectomy Pelvic lymph node dissection (PLND) accompanied by frozen section pathological examination Standard pelvic lymphadenectomy is limited Extended pelvic lymphadenectomy  Incidence of lymph node metastases increased from 10% to 26.2% Heidenreich et al. J Urol. April 2002.

10. Extended lymph node dissection  Obturator nerve injury  Trauma to major vessels Narayan et al. Urology 1994;44:519–24. Frozen section pathologic analysis has false negative rate of 30–40% Young et al. J Clin Path 52,1999.

11. 11 Current Need Non-invasive technique Non-invasive technique that detects and characterizes LN with high degree of sensitivity and specificity Broad anatomic coverage Broad anatomic coverage for all LN

12. Combidex (ferumoxtran-10) Nanoparticles Size: 21 nm R1: 17 mMsec-1 R2: 48 mMsec-1

13. Uptake by normal lymph nodes Combidex (ferumoxtran-10)

14. 14 Technique 1.5 T MR systems using pelvic phase array coil (Siemens Magnetom, GE Horizon) Imaging time/sequences (25 minutes/patient)  T2 FSE sequences  T2* gradient echo sequences  3D gradient echo sequences Post-processing  3D reconstruction

15. Pre-contrast Post-contrast 24 hours

18. 20 mm

19. Unenhanced MR Combidex enhanced MR

20. 20 Clinical Impact  Improved clinical staging  Surgical planning  Radiation therapy planning  Image-guided intervention

21. COMBIDEX ® (ferumoxtran-10)