Combidex, MRI, and identification of nodal metastases

One of the major issues in the management of prostate cancer is the identification of early physical (as opposed to biochemical) evidence of metastatic disease.

For some years now, an imaging agent known as ferumoxtran-10 (Combidex) has been in development as a tool that helps to identify pelvic and extra-pelvic lymph node metastases in patients with progressive prostate cancer — long before these tiny metastases are otherwise evident using standard forms of magnetic resonance imaging (MRI) or computer-assisted tomography (CAT) scans. Combidex imaging has been approved for use in some European countries — but not in the USA.

A recent, multi-center study by Heesakkers et al. has evaluated the use of ferumoxtran-10 and MRI to detect and identify lymph node metastases occurring outside outside the normal area of pelvic lymph node dissection (PLND) in 296 patients with prostate cancer. All patients had intermediate to high risk for nodal metastases (PSA level > 10 ng/ml, Gleason score > 6, or stage T3 disease).

One day after infusion of ferumoxtran-10, the patients were given a pelvic MRI scan. All lymph nodes that appeared to be positive for nodal metastases were identified, and categorized as being within or outside the normal area of PLND.  Patients identified as having apparent nodal metastases were then given a CT-guided biopsy, a routine PLND, or an MRI-guided, minimal extended PLND to establish whether the lymph nodes were truly positive for metastatic prostate cancer.

The results of this study are as follows:

  • 58/296 patients (19.6 percent) showed clear indications of positive lymph nodes using the ferumoxatran-10 and MRI scan.
  • Of these 58 patients, 44 (75.9 percent) had histopathologic confirmation of lymph node metastases and in the remaining 18 patients (24.1 percent)  the initial imaging results could not be confirmed.
  • In 18/44 patients (41 percent), the initial imaging showed nodes to be exclusively outside the routine area of dissection, and this was confirmed by an MRI-guided, extended PLND (n = 13) or a CT-guided biopsy (n = 5).
  • In another 18/44 patients (41 percent), the initial imaging identified positive nodes inside and outside the routine area of dissection; routine PLND was used to confirm the nodes inside the routine area of dissection (n = 11) and CT-guided biopsy was used to confirm nodes outside the that area (n = 7).
  • In 8/44 patients, initial imaging showed positive nodes exclusively within the routine raea of dissection, and these were confirmed by PLND (n = 5) or by CT-guided biopsy (n = 3).

This study seems to demonstrate the dilemma that is presented by the use of ferumoxtran-10, and may explain why it has not yet been approved by the US Food & Drug Administration. There was a 24.1 percent false positive rate in this study, leading to unnecessary surgical intervention. That is a high false positive rate for a diagnostic test that is going to lead to any form of serious interventional treatment.

Perhaps the most appropriate question that researchers need to be asking based on the results of this trial is: Can we develop a “second generation” form of ferumoxtran-10 that will have a significantly lower rate of false positive findings? If we could, and the product has a high safety profile as an imaging agent, then there would seem to be little doubt that such an agent would be helpful in the early identification of nodal metastases in patients with intermediate- and high-risk disease.

2 Responses

  1. Please respond with status of development of a “second generation” form of ferumoxtran-10 and the availability of COMBIDEX MRI testing in USA … Thanks.

    Bill Garman

  2. Dear Mr. Garmin:

    Please see the more recent article on the demise of Combidex. We are not aware of any ongoing research on develpment of a “second generation” product at this time, and it is extremely unlikely that Combidex will ever be approved in the USA.

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