1. Clinical Utility of Combidex in Various Cancers
Jelle O. Barentsz, MD
Professor of Radiology
University Medical Center Nijmegen, Netherlands

2. Clinical Utility in Cancer
Post-Phase III peer reviewed publications
NEJM, Radiology
Blinded post-contrast image evaluation with histopathology
Impact on treatment planning
Areas where Combidex MRI provides significant clinical benefit
Prostate
Bladder
Head and Neck
Breast

3. Blinded Image Evaluation Pre-Contrast Post-Contrast
Published Studies
Primary Tumor
Patients
Nodes
Blinded Image Evaluation
Pre-Contrast Post-Contrast
Prostate
Harisinghani-NEJM-2003 80
334 X
Bladder
Deserno-Radiology-2004 58
172
Head and Neck
Mack-Radiology-2002 27
1029
Breast
Michel-Radiology-2002 20
296

4. Post-Contrast Results – Published Studies

5. Prostate Cancer
Current imaging has insufficient sensitivity for LN staging
Surgical LN Sampling
– Samples only a limited area
– 11–31% +LN outside sampled area
– Complications: 22% (open), 5% (lap)
– Lymphocele, lymphedema, DVT, PE, nerve damage, blood loss
Extended LN dissection detects more + LN
but increases morbidity
Zincke (Mayo), Walsh (JHH), Burkhard (Bern)

6. Prostate Cancer Imaging Performance – Patient Level
True
Positive
Negative
False
Pre-contrast 15 37 10 18
Post-contrast 33 45 2
NEJM 2003 Harisinghani

7. Prostate Cancer Impact on Treatment Planning
5/80 patients (6%)
Guided needle biopsy for solitary unenlarged (5–8 mm) positive LN on Combidex MRI
All 5 confirmed positive
9/80 patients (11%)
PLND extended outside usual field due to positive LN on Combidex images
All 9 confirmed positive
NEJM 2003 Harisinghani

8. Prostate Cancer 7 mm partly metastatic node outside surgical field
Biopsy positive → Androgen ablation

9. Prostate Cancer Possibly metastatic
1 mm metastasis in LN outside obturator fossa.

10. Bladder Cancer 24% LN positive despite negative preoperative imaging
Nodal metastases (N2-3, or >4) radically changes treatment options
Extended LN dissection
– Detects more LN
– Increases survival for minimal disease
– Does not sample all areas of LN
– Increases morbidity
Studer (Switzerland) Skinner (USC) Ghoneim (Egypt)

11. Bladder Cancer Imaging Performance – Nodal Level
172 LN (58 patients)
Pre
Post
p-Value
Sensitivity
76%
96%
<.001
Specificity
99%
95%
Accuracy
92%
PPV
97%
89%
NPV
91%
98%
<.01
10/12 normal size positive LNs
seen on post-Combidex MRI only
Radiology 2004 Deserno

12. Head and Neck Cancer
5 yr survival 91% (localized) and 63% (regional LN)
Status of cervical LN is vital for choice of therapy
25% LN positive despite negative preoperative imaging (contrast CT) as metastatic nodes are small (5–10 mm)
Radical neck dissection
– Commonly performed – Results in cosmetic deformity – Complication rate 36–54%

13. Head and Neck Cancer Imaging Performance – Nodal Level
1029 LN (27 Patients) %
Post
Sensitivity 86
59/69
Specificity
100
960/960
Accuracy 99
1019/1029
PPV
59/59
NPV
960/970
Combidex MRI on LN level accurate in 26/27 (96%) patients
26% had reduced extent of surgery
Radiology 2002 Mack

14. Head and Neck Cancer 12 mm node Normal
Neck dissection could have been avoided

15. Breast Cancer Sentinel Lymph Node Staging (SLN) – 3–10% false negative
The Sentinel Node is the only positive node in 61% of patients with positive LNs
– These patients all undergo axillary dissection – High rate of clinically significant complications

16. Breast Cancer Imaging Performance – Nodal Level
296 LNs (18 Patients)
Reader 1
Reader 2
Average
Sensitivity
83% (25/30)
73% (24/33)
78%
Specificity
97% (252/261)
96% (253/263)
96%
Accuracy
95% (277/291)
94% (277/296)
94%
PPV
74% (25/34)
71% (24/34)
72%
NPV
98% (252/257)
97% (253/262)
97%
Radiology 2002 Michel

17. Breast Cancer
Normal
Metastatic
Sentinel node +
Primary tumor

18. Summary: Clinical Relevance
Current techniques to detect positive LNs in prostate, bladder, head and neck, and breast cancer have significant limitations
Combidex MRI shows high sensitivity and specificity in these tumors
Combidex MRI may reduce the extent of surgery and morbidity
Combidex MRI identifies additional positive LNs for biopsy or image-guided extended dissection (improve staging)

19. Indication
Combidex® (ferumoxtran-10) is for intravenous administration as a contrast agent for use with magnetic resonance imaging (MRI). Combidex can assist in the differentiation of metastatic and non-metastatic lymph nodes in patients with confirmed primary cancer who are at risk for lymph node metastases.
The information provided by Combidex should be considered in conjunction with other diagnostic information and lymph node findings from Combidex images should be pathologically confirmed unless medically contraindicated.

20. COMBIDEX®
(ferumoxtran-10)