From Insights May 2014 Vol.17 Is.2 | Jelle Barentsz, M.D. By Jelle Barentsz, M.D. Professor of Radiology and
Chair of the Prostate MR-Center of Excellence in Nijmegen, Netherlands
Modern management of pelvic lymph node metastases leaves much room for improvement. We know that when men have enlarged lymph nodes (>8mm) detected on standard scans, (such as CT scan) they have a significantly lower five-year survival than patients with smaller nodes (< 8mm) . Thus detection and localization of cancerous lymph nodes followed by focused treatment may enable cure and reduce side effects [6-7].
The problem is that CT scans and conventional MRI scans miss the majority of lymph node metastases (about 70% of the time). This is because the most of the metastases are too small (< 8 mm) for the CT scan to visualize them . Choline PET scans are somewhat better but also are usually unable to detect metastatic nodes if they are smaller than 6 mm . This is because there needs to be a minimum amount of tracer present in the lymph node before it reaches the threshold of detectability. Some studies show that surgical removal of pelvic lymph nodes only finds the nodes 59% of the time . This is because the nodes are frequently located outside the surgical field. Finally, attempts to cover all the lymph nodes with a broad-based radiation field have limitations. Studies have shown that more than 50% of metastatic lymph nodes are outside the routinely prescribed radiation field  (Figure 1). Therefore, the effectiveness of standard lymph node radiotherapy leaves much room for improvement .
Studies evaluating intravenous Combidex® contrast in conjunction with MRI scanning indicate that normal lymph nodes can be distinguished from metastatic nodes even when the metastases are very small(>2 mm) [8-13]. Combidex-enhanced MRI scans have significant improvement of the detection of metastases compared to Choline PET scans. MRI with Combidex detected more metastatic nodes (738 vs 132) in more patients (23/29 vs 13/29) in smaller nodes (mean diameter 4.9 vs 8.4 mm)  (Figures 2 and 3).
Studies also indicate that a Combidex-enhanced MRI may obviate the need for surgical node dissection [2, 12] reducing both side effects and cost. A large prospective multicenter study demonstrated the cost-effectiveness [15, 16]. The accuracy of Combidex has also been favorably compared with predictive algorithms. [17-18]. Combidex opens up the possibility of doing selective radiation directed to these small, thus far undetected metastatic nodes . The hope is that this early intervention will result in increased cure rates and less side effects [7, 19].
Combidex has Numerous Potential Applications
As of the time of writing this article 580 publications have addressed the use of Combidex. Many of these studies have evaluated Combidex for its possible applications outside its role in the detection of lymph nodes. Such applications include the diagnosis of “vulnerable” arteriosclerotic plaque, improving the diagnosis of bone metastases, multiple sclerosis, brain tumors, and kidney diseases. Nineteen studies have been published on using Combidex for the detection of small (2-3 mm) lymph node metastases in any cancer [1-19].
About fifteen years ago Combidex first became available for human use. The data from primary pharmacokinetic studies, a Phase I study, and the data in a Phase II study consistently showed that it is safe and well tolerated and that it has no effect on immune function. So far two attempts have been made to register Combidex by the FDA in the United States for clinical lymph node imaging and two attempts were made in Europe by EMEA. All of these four attempts were unsuccessful due to suboptimal trial design, suboptimal statistics, and suboptimal central reading.
Resurrection of Combidex in Nijmegen
I was the first researcher/radiologist to show the value of Combidex and publish studies validating its cost-effectiveness [8, 10, 16]. Unfortunately, during the recent economic crisis, development of Combidex ceased altogether. It became completely unavailable in April 2010. However, along with the help of businessman and advocate, Orn Adelsteinsson, PhD., our university in Nijmegen has been able to purchase all rights to Combidex along with all the documents and files from the original manufacturer. As of February 2014 based on the Combidex-files and approved GMP-quality control by a certified body Combidex-MRI is available again for all patients in Nijmegen. □
Figure 1. Small LN metastases detected with MRI. Patient after prostatectomy and local radiation, with subsequent PSA rise to 0.4 ng.ml. (A) coronal and (B) axial USPIO sensitive MR images show small 3 mm LN metastases (within circle) in the common iliac region. This area is outside the routine RTOG CTV region, and is likely to be missed by lymph node dissection.
Figure 2. Size of LN metastases detected with 11C Choline PET/CT and MRI. Size of metastatic LN found with MRI (blue) and 11C Choline PET/CT (red). Below 7 mm LN metastases are better detected with MRI. More than 50% of LN metastases are < 5mm.
Figure 3. 11C Choline PET/CT and MRI. (A). 11C Choline PET/CT shows a large (>7mm) LN metastasis in the left para-aortic region. This node is 8 mm on (B) MRI (node indicated by “A”). Smaller LN metastases go undetected with PET/CT, but are detected with MRI.