High-resolution MRI with magnetic nanoparticles allows the detection of small and otherwise undetectable lymph-node metastases

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http://content.nejm.org/cgi/content/abstract/348/25/2491
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Volume 348:2491-2499 June 19, 2003 Number 25
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A correction has been published: N Engl J Med 2003;349(10):1010

Noninvasive Detection of Clinically Occult Lymph-Node Metastases in
Prostate Cancer
Mukesh G. Harisinghani, M.D., Jelle Barentsz, M.D., Ph.D., Peter F. Hahn,
M.D., Ph.D., Willem M. Deserno, M.D., Shahin Tabatabaei, M.D., Christine
Hulsbergen van de Kaa, M.D., Ph.D., Jean de la Rosette, M.D., Ph.D., and
Ralph Weissleder, M.D., Ph.D.

ABSTRACT

Background Accurate detection of lymph-node metastases in prostate cancer
is an essential component of the approach to treatment. We investigated
whether highly lymphotropic superparamagnetic nanoparticles, which gain
access to lymph nodes by means of interstitial–lymphatic fluid transport,
could be used in conjunction with high-resolution magnetic resonance
imaging (MRI) to reveal small nodal metastases.

Methods Eighty patients with presurgical clinical stage T1, T2, or T3
prostate cancer who underwent surgical lymph-node resection or biopsy were
enrolled. All patients were examined by MRI before and 24 hours after the
intravenous administration of lymphotropic superparamagnetic nanoparticles
(2.6 mg of iron per kilogram of body weight). The imaging results were
correlated with histopathological findings.

Results Of the 334 lymph nodes that underwent resection or biopsy, 63
(18.9 percent) from 33 patients (41 percent) had histopathologically
detected metastases. Of these 63 nodes, 45 (71.4 percent) did not fulfill
the usual imaging criteria for malignancy. MRI with lymphotropic
superparamagnetic nanoparticles correctly identified all patients with
nodal metastases, and a node-by-node analysis had a significantly higher
sensitivity than conventional MRI (90.5 percent vs. 35.4 percent, P<0.001)
or nomograms.

Conclusions High-resolution MRI with magnetic nanoparticles allows the
detection of small and otherwise undetectable lymph-node metastases in
patients with prostate cancer.

Source Information

From Massachusetts General Hospital and Harvard Medical School, Boston
(M.G.H., P.F.H., S.T., R.W.); and University Medical Center, Nijmegen, the
Netherlands (J.B., W.M.D., C.H.K., J.R.).

Drs. Harisinghani and Barentsz contributed equally to the article.

Address reprint requests to Dr. Weissleder at the Center for Molecular
Imaging Research, Department of Radiology, Massachusetts General Hospital,
Bldg. 149, 13th St., Rm. 5403, Charlestown, MA 02129-2060, or at
weissleder@helix.mgh.harvard.edu.

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Currently recruiting in clinical trial in Texas
http://www.clinicaltrials.gov/ct/gui/show/NCT00147238
A Validation Study of MR Lymphangiography Using SPIO, a New Lymphotropic
Superparamagnetic Nanoparticle Contrast

This study is currently recruiting patients.
Verified by M.D. Anderson Cancer Center September 2005
urpose

The objective of the study is to re-validate the accuracy of
ferumoxtran-10, a new ultra-small superparamagnetic oxide (USPIO)
particles, using currently available a high-resolution MR imaging
technique in patients with surgically resectable carcinomas of prostate,
penis, and urinary bladder in their initial staging work-ups.

In most, if not all, tumor staging work-up, the knowledge of nodal disease
(“N” staging) is important in treatment planning and predicting the
outcome of the treatment.

Conventional way to evaluate the nodal disease is based on the “size” on
CT, MRI, or ultrasound. Unfortunately, despite continuous improvement, the
accuracy of the current imaging techniques detecting metastatic nodal
disease is notoriously suboptimal and varies greatly depending on the
criteria. Surgical exploration, either by an open surgery for lymph nodes
dissection or a laparoscopy, is required for accurate “N” staging in some
urologic tumors.

The new, ultra-small superparamagnetic agent, iron oxide (SPIO) particles
(Combidex; ferumoxtran-10), is taken primarily by reticuloendothelial
system (RES) of the liver and spleen and lymph nodes following the initial
vascular distribution. Multiple pre-clinical and clinical studies have
shown that the contrast injected intravenously accumulates in the
lymphatic system and decrease the signal intensity of normal lymph nodes
on MRI. The recent feasibility studies conducted in human have also shown
promising results to detect the malignant nodes in patients with Head and
Neck tumors, breast carcinomas, and prostate carcinomas. The most recent
report from Massachusetts General Hospital has shown about 90 %
sensitivity and 98 % specificity in detecting the metastatic pelvic lymph
nodes in patients with prostate carcinomas with a 41 % sensitivity and 98
% specificity for the nodes less than 5 mm.

Bladder cancer, Genitourinary cancer, Prostate cancer
Drug: Combidex- MR contrast agent

Study Type: Interventional
Study Design: Diagnostic, Non-Randomized, Open Label, Uncontrolled, Single
Group Assignment, Efficacy Study
Further Study Details:

Expected Total Enrollment: 80

Study start: July 2005

1. MRI will be performed prior to and 24- 36 hours after intravenous
infusion of 2.6 mg/kg of ferumoxtran-10.
2. Location and degree of suspicion of all nodes noted on MR images
will be marked on a diagram for each lymphatic chain in the pelvis and
each nodal group or node, if possible, will be correlated with the
surgical pathology. Also any malignant nodes seen only during the surgery
will be noted.

A total of 80 patients will be recruited as follows.

Each patient will have two images. One with and one without
ferumoxtran-10, thus this is a paired experiment, where sensitivity on a
per patient basis is the major endpoint. The null hypothesis is that the
sensitivity of both images are the same versus the alternative that the
sensitivity of MRI with nano particles is greater than that for MRI only

Of the 80 patients we expect 40% or 32 to have lymph node metastasis.
Based on the Harisinghani et. al. study(1 Cool

, the sensitivity of MRI only
was 45% and that of MRI with nano particles 100%.

Given below is the power of the two-sided McNemar test to detect
differences in the sensitivities of the two paired images, using alpha =
..01.

Sensitivity Pre-contrast Sensitivity Post Contrast Power 0.40 .90 0.957*
0.40 .95 0.992 0.40 .99 0.999 0.45 .90 0.897 0.45 .95 0.980 0.45 .99 0.998
0.50 .90 0.814 0.50 .95 0.946 0.50 .99 0.995

*From the above table, 32 patients ( with lymph node metastasis) should be
sufficient to detect a significant ( P < .01) difference between a
sensitivity of 0.45 without contrast agent and a sensitivity of .90 with
ferumoxtran-10 using the McNemar test.

The sensitivity, specificity, accuracy, and positive and negative
predictive values will be calculated on a per patient basis and on a per
lymph node basis. The effect of tumor size on test accuracy will be
estimated ( 24).

Eligibility
Genders Eligible for Study: Both
Criteria

Inclusion Criteria:

1. Patients with newly diagnosed pelvic urological tumors, including
prostate carcinomas, bladder carcinomas, and penile carcinomas.
2. Planned to have a surgical exploration or a laparoscopy for pelvic
lymph node dissection/biopsy within 4 weeks.
3. No previous treatment.
4. Signed written consent and HIPAA authorization

Exclusion Criteria:

1. Contraindications for MRI
2. Claustrophobia, metals in the pelvis, previous pelvic surgery
3. Allergy or hypersensitivity to iron products, dextrans, iron-dextran
complex
4. Previous treatement related to the primay disease or any pelvic
surgery a. Prostate cancer: metastases demonstrated on preoperative
imaging; prior hormonal therapy greater than 3 months; prior local therapy
for prostate cancer b. Penile Cancer: prior systemic therapy for penile
cancer; prior inguinal radiation c. Bladder Cancer: prior systemic therapy
for bladder cancer (does NOT include intravesical chemotherapy or
immunotherapy); prior pelvic radiation; history of partial cystectomy or
prior pelvic lymph node dissection
5. Women of child-bearing potential. (Women who will be having
hysterectomy as part of bladder surgery will not be excluded.)
6. Clinically documented or risk of primary or secondary iron
overloading (e.g.History of thalassemia, sickle cell anemia, hereditary
hemochromatosis, multiple transfusions with any reason)

Location and Contact Information
Please refer to this study by ClinicalTrials.gov identifier NCT00147238

Haesun Choi, M.D. 713-792-8177 hchoi@di.mdacc.tmc.edu

Texas
The University of Texas M.D. Anderson Cancer Center, Houston,
Texas, 77030, United States; Recruiting
Haesun Choi, M.D. 713-792-8177 hchoi@di.mdacc.tmc.edu

Study chairs or principal investigators

Haesun Choi, M.D., Principal Investigator, University of Texas M.D.
Anderson Cancer Center

More Information
Study ID Numbers: 2004-0003
Last Updated: September 6, 2005
Record first received: September 6, 2005
ClinicalTrials.gov Identifier: NCT00147238
Health Authority: United States: Food and Drug Administration
ClinicalTrials.gov processed this record on 2005-09-30

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