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Contrast Media |
1 From the Department of Radiology, University of Washington School of Medicine, Box 357115, 1959 NE Pacific St, Seattle, WA 98195-7115 (Y.A., K.R.M., U.P.S.). The complete list of authors and their affiliations are at the end of this article. Received July 2, 2002; revision requested September 10; revision received October 29; accepted January 14, 2003. Address correspondence to Y.A. (e-mail: anzai@u.washington.edu).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: One hundred fifty-two patients were injected with ferumoxtran 10. Readers independently evaluated precontrast MR images by using node size criteria and subjective assessment of other imaging features. Ferumoxtran 10–enhanced MR images were evaluated alone and paired with precontrast images for comparison. The diagnostic performances of precontrast MR size criteria and postcontrast MR imaging were evaluated with receiver operating characteristic (ROC) analysis. Lymph node signal intensity was correlated with histopathologic findings. MR imaging and histopathologic nodal stages were compared.
RESULTS: Node-level sensitivity, specificity, and accuracy of precontrast MR imaging were 54%, 82%, and 68%, respectively, with node size criterion alone; 91%, 51%, and 71%, respectively, with subjective reader assessment; 85%, 85%, and 85%, respectively, with postcontrast MR imaging alone; and 83%, 77%, and 80%, respectively, with paired pre- and postcontrast MR imaging. Compared with size criteria, subjective reader assessment had higher sensitivity but substantially lower specificity. Areas under the ROC curve for pre- and postcontrast MR imaging were 0.76 and 0.83, respectively. Nonmetastatic nodes had significantly lower signal intensity than metastatic nodes on postcontrast T2-weighted MR images (P < .001). Postcontrast nodal staging was significantly more accurate than precontrast nodal staging (P < .01). Headache, back pain, vasodilatation, and urticaria each occurred in 6% of patients.
CONCLUSION: Ferumoxtran 10–enhanced MR imaging was safe and effective and facilitated improved diagnostic performance. Use of iron oxide–enhanced MR imaging increased the positive predictive value by 20% and the accuracy by 14% compared with reader assessment. Differentiating patients with no nodal metastatic involvement was more reliable with ferumoxtran 10–enhanced MR imaging than with precontrast MR imaging.
© RSNA, 2003
Index terms: Contrast media • Iron • Lymphatic system, MR, 99.129411, 99.129412, 99.129416, 99.12943 • Lymphatic system, neoplasms, 99.32, 99.33 • Magnetic resonance (MR), contrast enhancement, 99.12943
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Ferumoxtran 10 (Combidex; Advanced Magnetics, Cambridge, Mass) is a contrast agent consisting of ultrasmall superparamagnetic iron oxide particles that can enhance depiction of the normal function of the reticuloendothelial system at MR imaging. A lymph node with normal phagocytic function takes up a substantial amount of iron oxide particles and therefore markedly reduces the signal intensity (SI) following intravenous administration of iron oxide agents secondary to the magnetic susceptibility and T2 shortening effects of the iron oxide particles. Although tumoral uptake of ultrasmall iron oxide particles in intracranial tumors has been demonstrated (1–3), a metastatic lymph node incorporates iron oxide particles much less than a normal lymph node and maintains a relatively high SI. These differences in SI between normal and metastatic nodes can be easily detected visually.
The earlier works of Weissleder et al (4–6) and Lee at al (7) greatly contributed to the development of ultrasmall superparamagnetic iron oxide agents. Several investigators (8–13) have reported the efficacy of iron oxide agents in the differentiation of metastatic and normal lymph nodes in animal models. Ferumoxtran 10 is also referred to as AMI 227, AMI Code 7227, BMS 180549, Combidex, Sinerem (in Europe), and dextran-coated ultrasmall superparamagnetic iron oxide agent.
The objectives of this study were to determine the safety and efficacy of ferumoxtran 10 for diagnosis of lymph node metastases from head and neck, chest, breast, abdominal, and pelvic carcinomas and to determine the clinical usefulness of this agent in the nodal staging of these cancers.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Study Subjects
Of the total of 152 patients who received ferumoxtran 10, five were excluded from the study: two who received less than 80% of the correct dose, one who did not undergo MR imaging, one who was imaged incorrectly, and one who did not meet the study recruitment criteria. The remaining 147 patients were evaluable. For blinded interpretation of the MR images, the images obtained in six healthy subjects from a previous dose-ranging study (14) were included for assessment of truly normal cases; thus, a total of 153 subjects were included in this study. The 147 evaluable patients included 29 patients with head and neck cancer, 32 with lung or mediastinal cancer, 23 with breast cancer, 26 with abdominal cancer, and 39 with pelvic cancer. Two patients had abdominal and pelvic cancers.
Patient inclusion criteria were age older than 18 years, a confirmed primary cancer, and the possibility of nodal metastases. At least one lymph node had to be visible on the precontrast MR images. Pregnant or lactating women and patients with lymphoma or small cell lung cancer were excluded. Patients who had undergone radiation treatment of the area of interest within the previous 6 months also were excluded. Our entire study was approved by the institutional review board at each participating institution, where all patients signed informed consent forms.
Physical Characteristics and Administration of Ferumoxtran 10
The physical characteristics of ferumoxtran 10 have been described in detail (8,12,15,16). Briefly, ferumoxtran 10 was provided in the form of a lyophilized powder consisting of ultrasmall superparamagnetic iron oxide particles covered with low-molecular-weight dextran. The iron oxide core is a form of nonstoichiometric magnetite and is 4.3–6.0 nm in diameter; in a solution, the total particle diameter is 17–21 nm. Ferumoxtran 10 consists of biodegradable iron oxide particles that are metabolized in the same way as nonmagnetic iron dextran compounds; it enters the normal body iron pool in the metabolic pathway through transferrin, ferritin, hemosiderin, and hemoglobin.
To administer ferumoxtran 10, we diluted the agent with 50 mL of saline and infused it through a 5-µm filter at a rate of 4 mL/min. A dose of 2.6 mg of iron per kilogram was chosen on the basis of results of a phase II dose-ranging study (14).
MR Imaging
MR imaging was performed in three patients with a 0.2-T MR imaging unit, in one patient with a 1.0-T unit, and in the remaining 143 patients with a 1.5-T unit. The basic MR imaging protocol included the acquisition of transverse T1-weighted spin-echo (580/11 [median repetition time msec/echo time msec], 256 x 192 matrix, one to two signals acquired) and transverse T2-weighted fast spin-echo (4,000/102, echo train length of eight to 16, 256 x 192 matrix, two signals acquired) images in 130 patients and the acquisition of conventional T2-weighted spin-echo images in 17 patients. Transverse T2*-weighted gradient-echo images (266/102, 20° flip angle, two signals acquired) were acquired in all 147 patients. The section thickness was 4 mm for imaging the head and neck and 5 mm for imaging the other body regions. The field of view was 18–20 cm for the head and neck and 34–42 cm for the other parts of the body.
Interpretation of MR Images
To reduce observer bias and minimize interobserver variability, teams of radiologists and oncologists who were not involved in patient enrollment interpreted the MR images. Four teams—each consisting of one radiologist and one oncologist, both blinded to the clinical histories and histopathologic results—were involved in image interpretation. Two teams interpreted the head and neck MR images independently, and the other two teams interpreted the MR images of the other body regions. The radiologist evaluated each lymph node visualized on the images for the presence or absence of metastatic disease. The oncologist assigned the nodal stage in each patient during the reading session by using the information provided by the radiologist.
MR images, without identifying markings, were displayed on a computer screen at Bio-Imaging Technologies, Newton, Pa. The readers interpreted the precontrast images twice: by using size criteria alone (ie, size-based diagnosis) and by using size criteria with other imaging features (ie, subjective reader diagnosis). Lymph node size was measured by using an electronic caliper. A node larger than 10 mm in short-axis diameter was considered metastatic according to the size criteria. For subjective reader diagnosis, the radiologists were asked to determine the presence or absence of metastasis by using all features on the precontrast MR images that they considered relevant. Although this reading protocol may simulate the clinical reading of MR images without iron oxide contrast material, it, unlike the size criteria protocol, has not been validated in large clinical studies.
Diagnostic guidelines (Fig 1) were used to evaluate the iron oxide–enhanced MR images. The team of blinded readers initially evaluated the precontrast images alone; then they evaluated the pre- and postcontrast MR images together (ie, paired MR images). At least 2 weeks later, the blinded readers interpreted the postcontrast MR images alone. To reduce recall bias, the order of case presentations in each MR image interpretation session was randomized.
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Quantitative Analysis
SI was measured by calculating mean region of interest SI values and SDs for the lymph nodes, noise, and muscle seen on pre- and postcontrast MR images. These calculations were performed by the onsite investigators at each institution. A region of interest was placed to cover a whole node. Median percentage changes in SI were calculated as follows: (postcontrast median value - precontrast median value)/(precontrast median value).
Nodal Staging
The oncologists assigned the nodal stage in each subject on the basis of the MR image interpretations made by the radiologists. No additional clinical information, except primary tumor site, was provided to help determine nodal stage. The oncologists determined the nodal stage on the precontrast, paired, and postcontrast MR images by using the American Joint Committee on Cancer staging system. The MR results were correlated with the final histopathologic nodal stages.
Safety Evaluation
Safety evaluation was performed in the initial 152 patients who received ferumoxtran 10 injections. A physical examination was performed by a physician at each institution before and after intravenous administration of ferumoxtran 10. Vital signs (ie, systolic and diastolic blood pressures, heart rate, respiratory rate, and body temperature) were recorded before and immediately, 15 minutes, 30 minutes, and 1 hour after the ferumoxtran 10 injection was started. Vital signs were also checked when the patient returned for postcontrast MR imaging 24–36 hours after ferumoxtran 10 administration. Blood testing and urinalysis were performed before and 24–36 hours after ferumoxtran 10 administration. Blood tests included complete blood count, blood chemistry, electrolyte, hepatic function, clotting function, and iron metabolism measurements.
Any abnormal vital signs or unexpected blood test results were followed up until they returned to baseline values. All adverse events were documented and followed up clinically until the patient’s condition returned to baseline status.
Statistical Analysis
For efficacy data evaluation, the McNemar test was used to assess differences between the pre- and postcontrast MR images and between the precontrast and paired MR images at node- and patient-level analyses. Nodal staging data also were analyzed by using the McNemar test. The Wilcoxon signed rank test was used to analyze the median values of lymph node SI on the pre- and postcontrast MR images. For safety data evaluation, the Wilcoxon signed rank test was used to analyze changes in vital signs and in laboratory findings. P < .05 was considered to indicate a significant difference in all statistical analyses.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Efficacy Evaluation
Overall diagnostic accuracy.—The sensitivity, specificity, and accuracy of the blinded MR imaging–based diagnoses made at node-level analysis by using (a) size criteria at precontrast MR imaging, (b) subjective reader assessment at precontrast MR imaging, (c) paired pre- and postcontrast MR imaging, and (d) postcontrast MR imaging only are shown in Table 1. The sensitivity achieved by using size criteria was low (54%), but specificity was high (82%). Subjective reader assessment resulted in increased sensitivity, to 91%, but decreased specificity, to 51%. These findings indicate that the blinded readers tended to diagnose more of the small nodes as metastatic.
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Node-level positive and negative predictive values.—The positive predictive values (PPVs) and negative predictive values (NPVs) of size criteria and subjective reader assessment at precontrast MR imaging, postcontrast MR imaging alone, and paired MR imaging are shown in Table 2. For size criteria at precontrast MR imaging, PPV was 74% and NPV was 65%. With postcontrast MR imaging, both PPV (84%) and NPV (84%) improved.
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Diagnostic accuracy of MR imaging of each anatomic region.—The efficacy of ferumoxtran 10–enhanced MR imaging of each anatomic region is illustrated in Figure 3. Results, particularly those obtained at precontrast MR imaging, varied among the anatomic regions. The overall accuracy of postcontrast MR imaging of the head and neck was 93% (average of 94% [47 of 50 nodes] and 92% [33 of 36 nodes] for readers 1 and 2, respectively), a significant improvement from the accuracy achieved at precontrast MR imaging: 69% (average of 76% [47 of 62 nodes] and 61% [28 of 46 nodes] for readers 1 and 2, respectively) with size criteria and 80% (average of 82% [51 of 62 nodes] and 78% [36 of 46 nodes] for readers 1 and 2, respectively) with subjective reader assessment. The overall accuracy of postcontrast MR imaging was 83% (average of 85% [27 of 32 nodes] and 82% [28 of 34 nodes] for readers 1 and 2, respectively) in the abdomen and pelvis, 82% (average of 80% [45 of 56 nodes] and 85% [49 of 58 nodes] for readers 1 and 2, respectively) in the breast, and 73% (average of 77% [24 of 31 nodes] and 68% [13 of 19 nodes] for readers 1 and 2, respectively) in the chest and mediastinum (Fig 4).
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Subjective reader assessment at precontrast MR imaging for the chest and abdomen-pelvis had high sensitivity but very limited specificity. Ferumoxtran 10–enhanced MR imaging, however, had fairly constant sensitivity and specificity (>80%) in the abdomen and pelvis with the same readers.
Patient-level analysis.—The diagnostic accuracy of postcontrast MR imaging was also analyzed on a patient basis. Patient-level analysis involved the patients who had undergone surgery or biopsy. The histopathologic findings in all nodes that were removed were correlated with the characteristics of all nodes that were visible at MR imaging. The sensitivity, specificity, PPV, and NPV of MR imaging at patient-level analysis are shown in Tables 3 and 4. The sensitivity of paired MR imaging (85%) was higher than that of size criteria (77%) (P < .05) (Table 3). The readers were able to correctly identify most patients who had at least one lymph node metastasis, regardless of whether they were evaluating pre- or postcontrast MR images. Therefore, there was no significant improvement in sensitivity with ferumoxtran 10 administration, as compared with the sensitivity of subjective reader assessment (at precontrast MR imaging).
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SI measurement.—The SI of the metastatic and nonmetastatic lymph nodes on precontrast T1-weighted spin-echo MR images increased after ferumoxtran 10 administration. The SI of lymph nodes on precontrast T2-weighted spin-echo and T2*-weighted MR images decreased after ferumoxtran 10 administration, as shown in Table 5. The metastatic nodes showed a greater increase in SI on the T1-weighted MR images than the nonmetastatic nodes (P < .001). The SI decreases in the nonmetastatic nodes on the T2- and T2*-weighted images were greater than those in the metastatic nodes; the most noticeable difference was measured on the T2*-weighted images (P < .001).
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Physical examination.—Six of 152 patients had changes in physical examination results from the baseline findings at the time of MR imaging performed 24–36 hours after ferumoxtran 10 administration. For four of these six patients, the change in physical examination results, including resolution of a restless foot in one patient, resolution of chest crackles in two patients, and stiff knees in one patient, was thought to be unrelated to ferumoxtran 10 infusion. Two of these patients had resolving urticaria, which was reported as an adverse event.
Vital signs.—There was no significant change in body temperature from the baseline temperature at any time in any patient. The mean values for systolic blood pressure, diastolic blood pressure, and respiratory rate decreased steadily from the baseline during the course of the study (P < .05, Wilcoxon signed rank test). The magnitude of these decreases was small: by 2–3 mm Hg for blood pressure and by 0.2–0.3 breaths per minute for respiration rate. Heart rate decreased by about one beat per minute during the first 30 minutes after contrast material administration and returned to baseline by 24–36 hours.
Laboratory tests.—Overall, laboratory tests revealed no effect of ferumoxtran 10 on routine serum chemistry, hematologic, or urinalysis values. Because the principal ingredient and active component of ferumoxtran 10 is iron oxide, the iron metabolism data reflected the amount of iron distributed in the body at contrast agent administration, as expected. The amount of iron oxide administered is less than that in a unit of blood, and the changes in stored iron levels caused by contrast agent administration are not enough to cause iron overload in a patient with normal iron levels.
As expected, the mean values for serum iron, total iron binding capacity, and percentage saturation increased significantly (P < .05) from baseline in the 24–36 hours following contrast agent administration. The mean serum ferritin level increased minimally and the mean serum transferrin level decreased minimally during this 24–36-hour period. All significant changes from baseline reflected the distribution of and metabolism induced by iron from ferumoxtran 10.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Nodal staging improved significantly with iron oxide enhancement, with which a substantial number of patients in whom precontrast MR imaging findings indicated NX received an accurate diagnosis of N0 or N positive. Moreover, many of the patients with questionable nodal metastasis received an accurate diagnosis of N0 at postcontrast MR imaging; these cases reflected increased diagnostic confidence. In addition, there was a significant difference in SI between the metastatic and nonmetastatic lymph nodes on T2-, T2*-, and T1-weighted MR images.
Several reports (17–23) have addressed the efficacy of ferumoxtran 10 for MR imaging of the head and neck, chest, abdomen, and pelvis. In a phase II trial of ferumoxtran 10, the diagnostic performance of MR imaging with this agent, which yielded a sensitivity of 95% and a specificity of 84% in the head and neck, was higher than that of conventional MR imaging (17). These results are close to those achieved in the present phase III clinical trial: sensitivity of 96% (average of 96% [25/26] and 96% [24/25] for readers 1 and 2, respectively) and specificity of 87% (average of 92% [22/24] and 82% [9/11] for readers 1 and 2, respectively) at postcontrast MR imaging of the head and neck. Results of a study (21) of head and neck cancer showed higher diagnostic performance at MR imaging performed with ferumoxtran 10 than at MR imaging performed without it. A study (20) of abdominal and pelvic malignancies revealed ferumoxtran 10–enhanced MR imaging to have 93% sensitivity and 100% specificity. In a study (18) to investigate the efficacy of iron oxide contrast agents in patients with urologic and pelvic cancers, a sensitivity of 100% and a specificity of 80% were reported. A sensitivity of 88% and a specificity of 77% were achieved in a European phase III clinical trial of ferumoxtran 10 (30).
The nodal staging of cancer has a major influence on therapeutic decisions. When an imaging examination depicts a single suspicious metastatic node, biopsy, surgical resection, radiation therapy, chemotherapy, or a combination of all of these treatments is performed. The dilemma occurs when the lymph nodes seen at imaging or physical examination appear normal (24–26). Some patients with such findings, who are judged to have N0 disease, have metastatic nodes, and some of them do not. In the studies (27,28) to reevaluate size criteria for head and neck cancer, 39% of patients with N0 disease at ultrasonography had metastatic nodes at surgery.
When, if ever, is observing patients who have N0 disease without administering medical treatment for nodal disease considered acceptable management? How reliable should an imaging examination be to be considered clinically acceptable? These questions have yet to be answered definitively. Some investigators (29) have reported that the NPV in a population with a high prevalence of the disease being evaluated has to exceed 90%–95%. The NPV of iron oxide–enhanced MR imaging was not that high in this study. The false-negative rate was not negligible. We need to further investigate the false-negative cases and the potential reasons why ferumoxtran 10–enhanced MR imaging did not depict some metastatic lymph nodes. Some false-positive diagnoses of nodes are expected because granulomatous disease or infection can reduce the phagocytic activity of lymph nodes, mimicking metastatic nodes. Such false-positive nodes appear to be more of a problem in patients with chest or mediastinal disease. In two studies of the efficacy of ferumoxtran 10 at MR imaging of lung cancer, the specificities were different: 80% in one study (22) and 38% in the other (23).
In this study, we evaluated a subjective diagnostic method, reader assessment at precontrast MR imaging, and compared it with iron oxide–enhanced MR imaging. Reader assessment–based diagnoses might closely reflect how radiologists perform in their practices. As demonstrated in Tables 1 and 2, the radiologists performing these subjective interpretations tended to diagnose metastasis in nodes that were smaller than those that they diagnosed as metastatic by using size criteria. Because these blinded readers lowered their threshold for the diagnosis of metastatic nodes, specificity was sacrificed. Without a definitive diagnostic study, "overdiagnosing" may be a practical trade-off to avoid excluding treatment from some patients with cancer. Overdiagnosing metastatic nodes in some patients with cancer may cause less harm than missing metastatic nodes, but it results in large numbers of patients with N0 lesions undergoing unnecessary treatment for possible metastatic disease.
At both pre- and postcontrast MR imaging, node-level analysis yielded better results than patient-level analysis. The sensitivity of paired MR imaging was higher than that of precontrast MR imaging size criteria, and the specificity of postcontrast MR imaging was significantly improved (P < .001) compared with that of precontrast MR imaging–based reader assessment at patient-level analysis and thus led to fewer false-positive cases. However, the NPV of postcontrast MR imaging was not significantly improved compared with that of precontrast MR imaging. The European phase III trial (30) also revealed that the specificity and PPV for postcontrast MR imaging were higher than those for precontrast MR imaging; however, the sensitivity and NPV of precontrast MR imaging were high and did not improve following iron oxide–based contrast material administration. These results indicate that ferumoxtran 10 greatly reduced the number of false-positive cases, but not the number of false-negative cases, in this phase III clinical trial.
One potential source of false-negative cases was owing to the presence of a nodal mass conjoined with a primary tumor. This might have been a case in which the radiologist assigned a diagnosis of no nodal metastases but the pathologist observed residual nodal structures adjacent to the primary tumor and thus assigned a diagnosis of conglomerated metastatic nodes. This common problem is independent of the use of iron oxide contrast agents and is seen more often in chest and mediastinal tumor cases. Improved spatial resolution at imaging may be required to resolve this problem in the future. Since the NPV was not significantly improved on a patient level in this study, one could argue that the number of unnecessary biopsies or surgical nodal dissections does not decrease with the use of ferumoxtran 10. Whether the use of ferumoxtran 10 substantially affects the treatment of patients with cancer needs to be specifically investigated in large prospective clinical studies after this agent becomes widely available.
Our SI measurements indicated substantial T1 and T2 relaxation mechanisms of ferumoxtran 10 in metastatic and normal nodes. As we expected, the T2 shortening effect was substantially more apparent in the normal nodes. The metastatic nodes had a greater increase in SI than the normal nodes on T1-weighted spin-echo MR images. It has been shown that ultrasmall superparamagnetic iron oxide particles are taken up by peripheral experimental gliomas in rodent models (2,3). Uptake of ferumoxtran 10 in human brain tumors has also been reported (1). Although the results of studies demonstrate iron oxide particle uptake in the cytoplasm of tumor cells, the degree of uptake is variable among brain tumors and much less than that in organs and structures of the reticuloendothelial system, such as lymph nodes. In our study, the increased SI in metastatic lymph nodes at T1-weighted MR imaging could have been due to either the uptake of iron oxide by tumor cells or a lack of relative T2 shortening effect in the metastatic nodes.
The findings in this phase III clinical trial demonstrate how nodal staging can change with the use of ferumoxtran 10. Blinded clinical oncologists working together with blinded radiologists were asked to determine nodal stages on the basis of the radiologists’ reading of precontrast, postcontrast, and paired MR images. We found it interesting that the nodes diagnosed as NX at precontrast MR imaging were more definitively and accurately staged with iron oxide enhancement. These findings may have reflected the radiologists’ increased confidence in their assessments regarding the presence or absence of metastasis. More than 70% of patients who received a diagnosis of N positive (ie, having metastatic disease) with precontrast MR received a diagnosis of N0 (ie, no metastatic disease) with postcontrast MR, which was proved to be accurate at histopathologic correlation. This effect of ferumoxtran 10 on nodal staging should be further investigated in large clinical studies.
The limitations of iron oxide–enhanced MR imaging in clinical practice include the requirement to obtain images at 24–36 hours after contrast material administration. For fiscal and logistic reasons, the acquisition of two MR images is a major drawback in current practice. The results of this study did not show a significant difference in diagnostic performance between postcontrast only and paired MR imaging, suggesting that it might be sufficient to obtain postcontrast images only. However, patients still have to receive the injection the day before, similar to patients undergoing some nuclear medicine studies. To consider this possible modification to the imaging protocol, it is necessary to further investigate the iron oxide–enhanced MR imaging appearances of primary tumors and other anatomic structures. Iron oxide–based contrast material is administered by means of drip infusion, which takes approximately 15–20 minutes to complete. The necessity of a nurse’s or physician’s presence at the time of infusion is also a subject for future discussion.
One of the limitations of the study design was the inclusion, for purposes of analysis, of patients who had undergone biopsy. Percutaneous biopsy occasionally involves sampling errors, which can cause analysis errors. Contrast-enhanced CT has been the imaging modality of choice for nodal metastasis detection in the majority of the body regions. Contrast-enhanced CT and iron oxide-enhanced MR imaging need to be compared to further evaluate what additional value this MR contrast agent has in the imaging work-up of patients with cancer.
Several minor adverse events (28%) were associated with ferumoxtran 10 administration in this study. This number was higher than those previously reported in the safety data from phase I and II clinical trials of ferumoxtran 10 (15,31). Most adverse events began within 1 hour after contrast agent administration, were mild to moderate in severity, and resolved within 24 hours. The most frequent adverse events were headache, back pain, urticaria, and vasodilatation, which were treated with acetaminophen and/or diphenhydramine without substantial consequences. These adverse events are somewhat similar to those related to the use of ferumoxides (Feridex IV; Berlex Laboratories, Wayne, NJ), which consists of larger iron oxide particles. In the phase III trial of ferumoxides (32), back pain was the most frequent adverse reaction, occurring in 4% of the subjects. Lumbar pain has also been reported to be associated with the intravenous administration of a variety of colloids and emulsions. The exact physiologic mechanism is not well understood but is hypothesized to be occlusion of microvascular structures of the paraspinal muscles, renal artery spasm, or allergic reaction.
In conclusion, ferumoxtran 10 is a safe and effective MR imaging contrast agent for the detection of nodal metastasis. MR imaging enhanced with this iron oxide agent yielded higher sensitivity and specificity compared with objective size criteria and subjective radiologist assessment (both at precontrast MR imaging). Ferumoxtran 10 administration facilitated improved accuracy in the diagnosis of N0 disease. However, whether MR imaging enhanced with this agent can facilitate changes in treatment management and help improve the clinical outcome of patients with cancer by enabling better characterization of nodal status remains to be determined.
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ACKNOWLEDGMENTS |
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Authors: Yoshimi Anzai, MD, Catherine W. Piccoli, MD, Eric K. Outwater, MD, William Stanford, MD, David A. Bluemke, MD, PhD, Pamela Nurenberg, MD, Sanjay Saini, MD, Kenneth R. Maravilla, MD, David E. Feldman, MD, Udo P. Schmiedl, MD, James A. Brunberg, MD, Isaac R. Francis, MD, Steven E. Harms, MD, Peter M. Som, MD, Clare M. Tempany, MD, Robert D. Harris, MD, Judith K. Amorosa, MD, Arun N. Sukerkar, MD, Robert J. Herfkens, MD, Patricia A. Hudgins, MD, Evan S. Siegelman, MD, Suresh K. Mukherji, MD, Vijay M. Rao, MD, Patricia J. Mergo, MD, Pablo R. Ros, MD, MPH, Peter L. Davis, MD, Joseph F. Mammone, MD, Jeffrey J. Brown, MD, Paula Jacobs, PhD, Marie R. Morris, MS, Laurie A. Loevner, MD, Kevin R. Fox, MD, Susan M. Campos, MD, Far Sean Leong, MD, Terese M. Weber, MD, David M. Yousem, MD.
Author affiliations: University of Washington School of Medicine, Seattle (Y.A., K.R.M., U.P.S.); Thomas Jefferson University Hospital, Philadelphia, Pa (C.W.P., E.K.O., V.M.R.); University of Iowa Hospitals and Clinics, Iowa City (W.S.); Johns Hopkins Medical Institutes, Baltimore, Md (D.A.B., D.M.Y.); University of Texas Southwestern Medical Center, Dallas (P.N.); Massachusetts General Hospital, Boston (S.S.); Medical University of South Carolina, Charleston (D.E.F.); University of Michigan Medical Center, Ann Arbor (Y.A., J.A.B., I.R.F., S.K.M.); University of Arkansas for Medical Sciences, Little Rock (S.E.H.); Mount Sinai Hospital, New York (P.M.S.); Brigham and Women’s Hospital, Boston, Mass (C.M.T., P.R.R.); Dartmouth-Hitchcock Medical Center, Lebanon, NH (R.D.H.); Robert Wood Johnson University Hospital, New Brunswick, NJ (J.K.A.); Illinois Masonic Medical Center, Chicago (A.N.S.); Stanford University Medical Center, Calif (R.J.H.); Emory University School of Medicine, Atlanta, Ga (P.A.H.); University of Pennsylvania Medical Center, Philadelphia (E.S.S., L.A.L., K.R.F.); University of North Carolina School of Medicine, Chapel Hill (S.K.M.); University of Florida College of Medicine, Gainesville (P.J.M., P.R.R.); University of Pittsburgh Medical Center, Pa (P.L.D.); Cooper University Medical Center, Camden, NJ (J.F.M.); Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, Mo (J.J.B.); Advanced Magnetics, Cambridge, Mass (P.J., M.R.M.); Bracco Diagnostics, Princeton, NJ (M.R.M.); Gillette Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, Mass (S.M.C.); Lahey Clinic, Burlington, Mass (F.S.L.); and University of Alabama at Birmingham (T.M.W.).
Y.A., S.E.H., and E.S.S. have served as consultants to Advanced Magnetics in the past; P.R.R. is a consultant to Advanced Magnetics; P.J. is an employee of and minor stockholder in Advanced Magnetics; and M.R.M. was an employee of Advanced Magnetics at the time of this study.
Author contributions: Guarantors of integrity of entire study, Y.A., P.J., F.S.L.; study concepts, S.S., K.R.M., P.M.S., V.M.R., M.R.M., L.A.L.; study design, Y.A., S.S., K.R.M., V.M.R., P.J., M.R.M.; literature research, Y.A., L.A.L.; clinical studies, Y.A., C.W.P., E.K.O., W.S., D.A.B., P.N., K.R.M., U.P.S., J.A.B., I.R.F., S.E.H., P.M.S., C.M.T., R.D.H., J.K.A., A.N.S., R.J.H., P.A.H., S.K.M., P.J.M., P.R.R., J.F.M., J.J.B., M.R.M., L.A.L.; experimental studies, C.W.P.; data acquisition, C.W.P., E.K.O., W.S., D.A.B., P.N., S.S., K.R.M., U.P.S., J.A.B., C.M.T., R.D.H., A.N.S., R.J.H., S.K.M., P.R.R., J.F.M., J.J.B., M.R.M., L.A.L., T.M.W., D.M.Y.; data analysis/interpretation, Y.A., C.W.P., D.A.B., P.N., K.R.M., D.E.F., J.A.B., R.D.H., A.N.S., E.S.S., J.F.M., P.J., M.R.M., L.A.L., K.R.F., S.M.C., F.S.L., D.M.Y.; statistical analysis, P.J.; manuscript preparation, Y.A., K.R.M., J.A.B., P.J., M.R.M.; manuscript definition of intellectual content, Y.A., K.R.M., P.M.S., P.A.H., M.R.M.; manuscript editing, E.K.O., W.S., D.A.B., K.R.M., I.R.F., R.D.H., P.A.H., E.S.S., J.F.M., J.J.B., L.A.L.; manuscript revision/review, Y.A., C.W.P., W.S., D.A.B., P.N., S.S., K.R.M., D.E.F., U.P.S., J.A.B., I.R.F., P.M.S., C.M.T., R.D.H., A.N.S., R.J.H., E.S.S., S.K.M., V.M.R., P.R.R., P.L.D., J.F.M., J.J.B., P.J., M.R.M., L.A.L., K.R.F., D.M.Y.; manuscript final version approval, W.S., D.A.B., P.N., S.S., K.R.M., D.E.F., J.A.B., I.R.F., S.E.H., P.M.S., A.N.S., V.M.R., P.R.R., J.F.M., P.J., M.R.M., L.A.L., K.R.F., D.M.Y.
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