Ferumoxtran-10: An Important New
Prostate Cancer Staging Tool

PCRI Insights November 2004 vol. 7, no. 4

By Maha Torabi, MD and Mukesh G. Harisinghani, MD, Department of Radiology, Massachusetts General Hospital, Boston, MA

Introduction
Evaluation of lymph nodes has important therapeutic and prognostic significance in patients with newly diagnosed prostate cancer. Patients with truly localized disease and with no lymph node involvement have varying treatment options available which include radical prostatectomy, watchful waiting, or radiotherapy whereas the patients with locally advanced and metastatic disease are usually treated with adjuvant androgen-deprivation and radiation therapy.1-3 Thus, it is important to have a sensitive and reliable means of detecting lymph-node metastases in men with prostate cancer.

Now, studies by American and Dutch researchers indicate that high-resolution magnetic resonance imaging using an iron-oxide-containing contrast agent offers the ability to produce a very accurate localization of tumor lymph node metastases in prostate cancer patients. This new imaging technique allows us to clearly distinguish between benign and malignant nodes and to construct three-dimensional maps to guide clinicians.

Prostate Lymphatic Drainage
The primary lymphatic vessels from the prostate gland drain into the regional lymph nodes of the true pelvis. These include the internal iliac (hypogastric), obturator, sacral, peri-vesical, and external iliac lymph node (See Figure 1).* Occasionally, metastases go beyond regional lymph nodes and involve distant lymph nodes outside the true pelvis. Distant lymph nodes include deep and superficial inguinal, common iliac, retro-peritoneal (aortocaval nodes), supra-clavicular, cervical and scalene nodes. Involvement of these distant lymph nodes stages the disease as node-positive (N+), and the patient would be considered stage M1A.

Surgical Lymph Node Staging
Pelvic lymph node dissection (PLND) followed by histological evaluation is the current “gold standard” for evaluating the presence of cancer in pelvic lymph nodes in patients with prostate cancer. This procedure can be performed either as an open procedure or using a laparoscopic technique. Either way, this method is invasive and has several shortcomings:

• The commonly performed nodal dissection is limited to the external iliac and obturator nodes. Metastases in nodes outside the sampling area (e.g. hypogastric, pre-sacral, and common iliac nodes) can be missed.
  
• Nodal dissection can also lead to post-surgical morbidity and complications, some of which include nerve injury, seroma, lymphocele and injury to blood vessels.
  
• The accuracy of the nodal sampling also is limited by the frozen analysis performed at the time of surgery. In a reported study by Davis et al4 that evaluates the histological analysis of intraoperative frozen section of lymph nodes, false-negative results as high as 33% were reported in pelvic node analysis of prostate cancer patients.

Current Lymph Node Imaging Techniques
A normal lymph node measures less than 1 cm in size, is ovoid, has a smooth and well-defined border, and shows a uniform, homogeneous density or signal intensity. Lymph nodes in different areas of the body require different imaging techniques to adequately assess their shape, contour, and intrinsic architecture.

Conventional ultrasound detects enlarged lymph nodes with high sensitivity and moderate specificity in head and neck cancers, but in PC patients it is difficult to visualize the deep pelvic lymph nodes. Positron emission tomography offers functional information regarding tissue activity, thereby providing superior staging information, but it has not been useful in detecting nodal metastasis in patients with PC due to the low metabolic activity of PC tissue. Computed Tomography (CT) and Magnetic Resonance (MR) both use cross sectional imaging and rely primarily on lymph node size. CT is the most widely used modality to detect and characterize lymph nodes in the initial staging of PC, but MR imaging has better soft tissue resolution and can better identify lymph nodes.

Non-invasive nodal characterization using cross sectional imaging (CT or MRI) relies primarily on lymph node size. Additional features such as nodal shape, contour and intrinsic architecture may occasionally provide additional information. Some benign nodes have a central fatty hilum that has a distinctive feature on CT and MRI.

The efficacy of using size criteria depends heavily on selecting a threshold, and this necessitates a tradeoff between setting (1) a low size threshold (highly sensitive but poorly specific) and (2) a high size threshold (more specific at a cost of decreased sensitivity). A range of acceptable threshold sizes has been proposed, such as long-axis or short-axis diameter, and application to specific nodal groups.6 However, studies using sizes derived from imaging and gross specimens demonstrate that a traditional size approach frequently overlooks metastasis, particularly when the metastasis involves only microscopic or partial infiltration of the lymph node.7 The specificity of size criteria also deteriorates due to benign inflammatory or infectious lymph node enlargement. If size criteria alone are used in the assessment of regional lymph node metastasis, MR and CT are comparable with moderate sensitivity and specificity.

With tumor infiltration, the long-to-short axis ratio of the lymph nodes decrease and they become more rounded. A commonly used size threshold in the pelvis accounts for this change in morphology, using 10mm in short axis diameter for ovoid lymph nodes while using a smaller threshold (8mm) as a cutoff in rounded lymph nodes.6

Application of these size and morphologic criteria requires the detection of lymph nodes using CT and MRI. This task can be complicated by motion, the presence of adjacent structures, and limitations in resolution. Continued technological development of innovative hardware will improve detection of lymph nodes in increasingly efficient ways; however, even improved detection may not be sufficient to optimize the performance of these modalities without a better means of lymph node characterization.

Nano-particle Enhanced MRI
A new class of MR contrast agent was developed in the 1980s for MR lymphography.8 Ultra-small super-paramagnetic iron oxide particles, known generically as ferumoxtran-10 or USPIO, and commercially as Sinerem® in the Netherlands (Laboratoire Guerbet, Aulnay sous Bois, France), and as Combidex® in the U.S. (Advanced Magnetics, Cambridge, MA) have been successfully evaluated for improved lymph node metastases detection in various clinical trials. 9-11 (Combidex® is not yet fully approved by the FDA.)

Ferumoxtran-10 nano-particles have a super-paramagnetic iron oxide core and contain a dense packing of dextrans to prolong their time in circulation (see Figure 2). For intravenous administration on an out-patient basis, the freeze-dried iron oxide is reconstituted in normal saline and injected at a dose of 2.6 mg of iron per kilogram of body weight over a period of 15 to 30 minutes. This method of lymphography requires two MRI scans performed 24 hours apart. The first MRI scan is done to evaluate the existence and location of the lymph nodes. Twenty-four hours after the injection of the contrast, the second MRI is done to evaluate contrast enhancement of the identified lymph nodes.

Following injection, the nano-particles slowly escape from the vessels into the interstitial space, from which they are transported to lymph nodes by way of lymphatic vessels. Within the lymph nodes, the particles are internalized by macrophages, and these intra-cellular iron-containing particles cause changes in magnetic properties that can be detected by MRI. The end result is that ferumoxtran-10 is a “negative” contrast agent, one that is taken up by benign lymph nodes with preserved nodal architecture; this “negative enhancement” appears as decreased signal intensity on T2 and T2*-weighted images. In contrast, areas of metastatic infiltration lack reticulo-endothelial structure and do not take up ferumoxtran-10 so there is a lack of uptake in all or part of a malignant lymph node. There is a spectrum of nodal enhancement pattern after ferumoxtran-10 administration pending on the nodal tumor burden; this spectrum ranges from homogenous darkening to complete lack of ferumoxtran-10 uptake (see Figure 3). Ferumoxtran eventually disintegrates, and the iron enters the iron metabolism cycle.

Reported Performance Results
Today, the reported accuracy of ferumoxtran-10 surpasses that of all the conventional techniques described earlier. In a recently published study, Harisinghani et al9 reported ferumoxtran-10-enhanced MRI significantly increased sensitivity for detection of lymph nodes, from 35.4% to 90.5%. Specificity was also increased, from 90.4% to 97.8%. This was particularly notable for the 45 of 63 metastatic lymph nodes that were identified with ferumoxtran-10 although these nodes did not meet the traditional size criteria needed to detect malignancy.

Anzai et al11, reporting on the overall phase III multi-center trial in evaluating various primary cancers, reported a sensitivity, specificity and accuracy of 85%, 85%, and 85%, respectively, with post-contrast imaging alone, and reported 83%, 77%, and 80%, respectively, with paired pre- and post-contrast MR imaging. The results of their study did not show a significant difference in diagnostic performance between post-contrast only and paired MR imaging, suggesting that it might be sufficient to obtain only post-contrast imaging for lymph node evaluation.

This high sensitivity and high specificity implied that the incidence of false positives and false negatives would be low. In fact, there were few reported false negative results, and these were usually due to microscopic foci of metastatic disease in small lymph nodes which are below the detection threshold of current MR scanners; and the few false positives were mainly due to reactive hyperplasia, localized nodal lipomatosis, and insufficient dosage of ferumoxtran-10.

Clinical trials have also documented the safety of this agent9,11 with the most common side effect being back pain, occurring in about 3-6% of patients; this is of uncertain origin and usually resolves when the infusion is temporarily ceased. Other less commonly reported minor side effects are a rash, transient decrease in blood pressure, and headache.

Conclusions
Assessment of lymph nodes is an important step in staging patients with prostate cancer. Although the current non-invasive techniques lack the accuracy needed, evolving technologies such as ferumoxtran-10-enhanced MR imaging allow us to improve the accuracy and clearly distinguish benign from malignant nodes. Although the cost and outcome benefits of MR imaging with lymphotropic super-paramagnetic nano-particles will have to be further studied in other, larger prospective clinical trials, we believe that this approach could provide significant clinical and cost benefits.

References
1. Walsh PC. Surgery and the reduction of mortality from prostate cancer. N Engl J Med 2002; 347:839-840.

2. Holmberg L, Bill-Axelson A, Helgesen F, et al. A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002; 347:781-789.

3. Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999; 341:1781-1788.

4. Davis GL. Sensitivity of frozen section examination of pelvic lymph nodes for metastatic prostate carcinoma. Cancer. 1995 Aug 15;76(4):661-8.

5. Liu IJ, Zafar MB, Lai YH, Segall GM, Terris MK. Fluorodeoxyglucose positron emission tomography studies in diagnosis and staging of clinically organ-confined prostate cancer. Urology. 2001 Jan; 57(1):108-11.

6. Jager GJ, Barentsz JO, Oosterhof GO, et al. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared rapid gradient-echo sequence. AJR Am J Roentgenol 1996; 167:1503-1507.

7. Tiguert R, Gheiler EL, Tefilli MV, et al. Lymph node size does not correlate with the presence of prostate cancer metastasis. Urology 1999; 53:367-371.

8. Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH, Josephson L. Ultrasmall superparamagnetic iron oxide: characterization of a new class of contrast agents for MR imaging. Radiology. 1990 May; 175(2):489-93.

9. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med. 2003 Jun 19;348(25):2491-9.

10. Taupitz M, Hamm BK, Barentsz JO, Vock P, Roy C, Bellin MF. Sinerem‚-enhanced MRI imaging compared to plain MR imaging in evaluating lymph node metastases from urologic and gynecologic cancers (abstr). Proceedings of the Radiological Society of North America, Chicago, IL; 1999; 387.

11. Anzai Y, Piccoli CW, Outwater EK, et al. Evaluation of neck and body metastases to nodes with ferumoxtran 10-enhanced MR imaging: phase III safety and efficacy study. Radiology. 2003 Sep; 228(3):777-88.

 

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