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Published online before print June 6, 2008, 10.1148/radiol.2482072039

(Radiology 2008;248:643.)

A more recent version of this article appeared on August 1, 2008
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© RSNA, 2008

Thoracic Imaging

Non–Small Cell Lung Cancer: Whole-Body MR Examination for M-Stage Assessment—Utility for Whole-Body Diffusion-weighted Imaging Compared with Integrated FDG PET/CT1

Yoshiharu Ohno, MD, PhD, Hisanobu Koyama, MD, Yumiko Onishi, MD, Daisuke Takenaka, MD, Munenobu Nogami, MD, Takeshi Yoshikawa, MD, Sumiaki Matsumoto, MD, Yoshikazu Kotani, MD, and Kazuro Sugimura, MD

1 From the Department of Radiology (Y. Ohno, H.K., D.T., T.Y., S.M., K.S.) and Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine (Y.K.), Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan; Division of Image-Based Medicine, Institute of Biomedical Research and Innovation, Kobe, Japan (Y. Onishi, M.N.); and Department of Radiology, Konan Hospital, Kobe, Japan (T.Y.). From the 2007 RSNA Annual Meeting. Received November 22, 2007; revision requested January 31, 2008; revision received February 10; accepted March 5; final version accepted March 18. Supported in part by Eizai, Philips Medical Systems, and the Knowledge Cluster Initiative of the Ministry of Education, Culture, Sports, Science and Technology, Japan. Address correspondence to Y. Ohno (e-mail: yosirad{at}kobe-u.ac.jp).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Purpose: To prospectively and directly compare the capability of whole-body diffusion-weighted (DW) imaging, whole-body magnetic resonance (MR) imaging with and that without DW imaging, and integrated fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for M-stage assessment in non–small cell lung cancer (NSCLC) patients.

Materials and Methods: The institutional review board approved this study; informed consent was obtained from patients. A total of 203 NSCLC patients (109 men, 94 women; mean age, 72 years) prospectively underwent whole-body DW imaging, whole-body MR imaging, and FDG PET/CT. Final diagnosis of the M-stage in each patient was determined on the basis of results of all radiologic and follow-up examinations. Two chest radiologists and two nuclear medicine physicians independently assessed all examination results and used a five-point visual scoring system to evaluate the probability of metastases. Final diagnosis based on each of the methods was made by consensus of two readers. Receiver operating characteristic (ROC) analysis was used to compare the capability for M-stage assessment among whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and PET/CT on a per-patient basis. Sensitivity, specificity, and accuracy were compared with the McNemar test.

Results: Area under ROC curve (Az) values of whole-body MR imaging with DW imaging (Az = 0.87, P = .04) and integrated FDG PET/CT (Az = 0.89, P = .02) were significantly larger than that of whole-body DW imaging (Az = 0.79). Specificity and accuracy of whole-body MR imaging with (specificity, P = .02; accuracy, P < .01) and that without DW imaging (specificity, P = .02; accuracy, P = .01) and integrated FDG PET/CT (specificity, P < .01; accuracy, P < .01) were significantly higher than those of whole-body DW imaging.

Conclusion: Whole-body MR imaging with DW imaging can be used for M-stage assessment in NSCLC patients with accuracy as good as that of PET/CT.

© RSNA, 2008


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Lung cancer is the most common cause of cancer-related death among both men and women worldwide (1). Non–small cell lung cancer (NSCLC) accounts for 80% of all lung cancers, and small cell lung cancer accounts for the remainder (2). The treatment regimen for NSCLC depends on preoperative TNM staging, with curative surgical resection possible for the early stages and chemoradiotherapy, chemotherapy, or best supportive care considered advisable for the later stages, depending on the patient’s performance status (3,4). Accurate tumor staging is therefore essential for choosing the appropriate treatment strategy, because it provides prognostic information and influences treatment options for patients with NSCLC.

Whole-body positron emission tomography (PET) with fluorine 18 fluorodeoxyglucose (FDG) has rapidly become accepted as the standard noninvasive modality for staging lung cancer in patients. Although PET has been shown to be superior to computed tomography (CT) for the staging of lung cancer, in reality PET and CT are complementary modalities whose combined diagnostic value is superior to that of either study alone (5). In addition, technologic advances have promoted integrated PET/CT as the new modality in the arsenal of cancer staging. Given the novelty of PET/CT, the number of studies involving the comparison of PET and PET/CT of NSCLC is still limited but is growing. Studies (6–8) have revealed the superior accuracy attained with integrated PET/CT over that with PET alone for overall staging and diagnosis of NSCLC.

Whole-body magnetic resonance (MR) imaging has been put forward as another whole-body technique for the assessment of distant metastases in patients with lung cancer, as well as those with breast cancer, malignant melanoma, and pediatric and other malignancies (9–14). Advantages of whole-body MR imaging include no need for ionizing radiation exposure, information from various sequences without and with administration of contrast media, improved temporal resolution due to a newly developed parallel imaging technique, a moving table scheme and/or multiple body-array coils, and suggested utility of MR imaging in various organs compared with CT and nuclear medicine studies. In addition, some investigators (15–20) have suggested that the diagnostic capability of MR imaging is equal to or better than that of standard radiologic examinations including contrast material–enhanced CT, bone scintigraphy, and/or FDG PET for the assessment of brain, bone, bone marrow, and adrenal gland metastases in oncology patients. Moreover, it has been suggested that diffusion-weighted (DW) imaging could be useful for the assessment of primary malignancy (21,22) and lymph node and/or distant metastases (23,24), as well as for detection of additional benign and/or malignant tumors (25,26), although DW imaging is widely utilized for evaluation of cerebral abnormalities (27–30). Diffusion is a physical property that describes the microscopic random movement of molecules in response to thermal energy. Also known as brownian motion, diffusion may be affected by the biophysical properties of tissues, such as cell organization and density, microstructures, and microcirculation. However, to our knowledge, no direct comparison has been made between the use of whole-body MR imaging with DW imaging and integrated FDG PET/CT in patients with NSCLC.

In this study, we attempted to validate the hypothesis that whole-body MR imaging with DW imaging has potential as an alternative technique for the detection of distant metastases in patients with NSCLC with a capability similar to that of integrated FDG PET/CT. However, in oncology patients, utilization of FDG PET or PET/CT has been limited to assessment of brain metastases in routine clinical practice. Therefore, direct comparison of the diagnostic accuracy for M-stage assessment with the inclusion of and with the exclusion of brain metastases is important for the determination of the actual utility of whole-body MR examinations. To this end, we prospectively and directly compared the capability of whole-body MR imaging with and that without DW imaging with that of integrated FDG PET/CT for M-stage assessment with the inclusion of and with the exclusion of brain metastases in patients with NSCLC and determined the utility of whole-body DW imaging as a component of whole-body MR examination for detection of metastases.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Protocol, Support, and Funding
This prospective study was approved by the institutional review board of Kobe University Hospital and was partly supported by Eizai (Tokyo, Japan) (Y. Ohno, K.S.), Philips Medical Systems (Best, the Netherlands) (Y. Ohno, K.S.), and the Knowledge Cluster Initiative of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Subjects
All patients were enrolled after they had been properly informed and had consented to participate in this study. A total of 227 consecutive patients (118 men, 109 women; mean age, 73 years), who were referred to our hospital with a diagnosis of NSCLC at pathologic examination and who were considered candidates for surgical resection, underwent prospective whole-body MR imaging with and that without DW imaging, integrated FDG PET/CT, and conventional radiologic imaging before treatment. All studies were performed in random order within 3 weeks of diagnosis and before treatment. Follow-up examinations were performed for more than 12 months after treatment.

The eventual study group of 203 patients (mean age, 72 years; age range, 47–85 years) comprised 109 men (mean age, 72 years; age range, 47–81 years) and 94 women (mean age, 72 years; age range, 49–85 years) because 24 patients were excluded due to insufficient or no follow-up examinations after treatment. The final diagnosis of NSCLC was made on the basis of findings from histologic examinations of specimens obtained by using transbronchial or CT-guided biopsy or on the basis of pathologic findings of resected specimens obtained at surgical resection at our hospital. There were 176 patients with adenocarcinomas, 19 with squamous cell carcinomas, and eight with large cell carcinomas.

Whole-Body MR Imaging
MR imaging was performed with two 1.5-T superconducting magnets (Gyroscan Intera or Achieva; Phillips Medical Systems) by using a moving tabletop and tabletop extender. A longitudinal field of view of 2000 mm and a transverse field of view of 530 mm were generated. For every examination, whole-body MR images were obtained in the coronal and sagittal planes with a body coil and a moving table. Four sequences were performed for whole-body MR imaging. One was an in-phase T1-weighted gradient-echo sequence (repetition time msec/echo time msec, 100/4.6; flip angle, 75°; 256 x 128 matrix; 512 x 256 reconstruction matrix; number of signals acquired, two), performed both with and without administration of contrast media. The second was an opposed-phase T1-weighted gradient-echo sequence (100/2.3; flip angle, 75°; 256 x 128 matrix; 512 x 256 reconstruction matrix; number of signals acquired, two) without contrast media. The third was a sequentially reordered half-Fourier multishot short inversion time inversion recovery (STIR) turbo spin-echo sequence (3200/60/inversion time msec, 150; echo train length, 165; 256 x 128 matrix; 512 x 256 reconstruction matrix; number of signals acquired, two). The fourth was a sequentially reordered half-Fourier single-shot STIR spin-echo echo-planar imaging sequence (5759/70/180; echo train length, 141; b values, 0 and 1000 sec/mm2; 256 x 128 matrix; 512 x 256 reconstruction matrix; number of signals acquired, four) for DW imaging. Coronal and sagittal whole-body MR studies were performed at seven contiguous stations with 32–56 consecutive 8-mm sections acquired at each station. The breath-holding technique was used for performing dual-phase T1-weighted gradient-echo and STIR sequences in the thorax, with eight sections acquired in the coronal and sagittal planes for each breath hold. During contrast-enhanced whole-body MR examination, a standard dose (0.1 mmoL per kilogram of body weight) of contrast material (gadoteridol, PuroHance; Eizai) was administered intravenously through an antecubital vein. All whole-body MR examinations were performed within less than 90 minutes (mean, 75.8 minutes; examination time range, 60–90 minutes). Images acquired in matching positions were automatically aligned to generate a seamless whole-body coronal and sagittal image with the aid of commercially available software (View Forum; Philips Medical Systems) and were subjected to an interactive workstation review.

Integrated FDG PET/CT Examination for Initial Staging and Follow-up Examination
All patients fasted for at least 6 hours before intravenous administration of FDG at a rate of 3.3 MBq/kg, and images were obtained from the skull to the midthigh 60 minutes after completion of the injection. All FDG PET/CT examinations were performed with a commercially available PET/CT scanner (Discovery ST; GE Healthcare, Milwaukee, Wis). The axes of the multidetector CT and PET systems were mechanically aligned so that the patient could be moved from the multidetector CT to the PET scanner gantry by simply changing the position of the examination table. The resulting PET and CT scans were coregistered with hardware. CT was performed from the head to the pelvic floor according to a standardized protocol with the following settings: 140 kV; 40 mA with auto mA; tube rotation time, 0.6 second per rotation; detector collimation, 16 x 1.25 mm; beam pitch, 1.675; section thickness, 3.75 mm; and reconstruction pitch, 3.27 mm (to match PET section thickness). Patients maintained normal shallow respiration during the acquisition of CT scans, and no iodinated contrast medium was administered. Immediately after unenhanced CT, PET was performed in the identical transverse field of view. The acquisition time was 2 minutes per table position.

All integrated PET/CT examinations were performed within 60 minutes. The CT data were resized from a 512 x 512 matrix to a 128 x 128 matrix to match the PET data so that the scans could be fused and CT-based transmission maps could be generated. PET data sets were reconstructed iteratively with an ordered-subsets expectation maximization algorithm and segmented attenuation correction (two iterations, 21 subsets) and with CT data. Coregistered scans were displayed by means of commercially available software (Fusion Viewer; Nihon Medi-Physics, Nishinomiya, Japan).

Conventional Radiologic Examination and Final Diagnosis of M Stage
The conventional radiologic examinations for M-stage assessment performed during the initial and the follow-up examinations included brain MR imaging with administration of contrast medium, contrast-enhanced whole-body CT, and bone scintigraphy.

The final M stage and metastasis of a given site were determined on the basis of the results of conventional radiologic, integrated FDG PET/CT, and whole-body MR examinations and on the basis of pathologic results from endoscopic, CT-guided, or surgical biopsies, as well as on the basis of results of follow-up examinations performed for more than 12 months in every patient. The lesions suspected of being metastases on the basis of initial radiologic examination results were diagnosed as metastases when the tissues were proved to be metastatic at pathologic examination or the lesions became larger during the follow-up periods or decreased in size after treatment. The lesions suspected of being metastases on the basis of initial radiologic examination results and that could not be diagnosed as metastatic sites at pathologic examination were observed for more than 12 months and diagnosed as nonmetastatic sites when no change in size was observed during the follow-up period of more than 12 months or during treatment periods. The final determination of M stage and metastasis of a given site was made by consensus at a conference attended by diagnostic radiologists, radiation oncologists, pathologists, oncologists, and surgeons with more than 11 years of experience (range, 11–28 years).

Image Analysis
All images were interpreted by means of a picture archiving and communication system (ShadeQuest; Yokogawa Electric, Tokyo, Japan).

To determine the diagnostic capability of whole-body MR imaging with and that without DW imaging for the assessment of M stage in patients with NSCLC, all whole-body DW images and whole-body MR images obtained with and those obtained without DW imaging were prospectively and independently interpreted by two chest radiologists, one with 6 years (H.K.) and the other with 14 years of experience (Y. Ohno), in random order. Both readers were blinded to all information about the results of integrated FDG PET/CT and conventional radiologic examinations. For the assessment of the capability of whole-body DW imaging, precontrast DW images in coronal and sagittal planes (total of two sequences) were interpreted. For the assessment of the capability of whole-body MR imaging without DW imaging, pre- and postcontrast in-phase T1-weighted gradient-echo, precontrast opposed-phase T1-weighted gradient-echo, and precontrast STIR turbo spin-echo images in coronal and sagittal planes (total of eight sequences) were interpreted. For the assessment of the capability of whole-body MR imaging with DW imaging, pre- and postcontrast in-phase T1-weighted gradient-echo, precontrast opposed-phase T1-weighted gradient-echo, precontrast STIR turbo spin-echo, and precontrast DW images in coronal and sagittal planes (total of 10 sequences) were interpreted. The presence or absence of metastases in the head and neck, thorax, abdomen and pelvis, and bone was assessed independently by the same radiologists. The probability of the presence of metastases on a per-patient basis was then evaluated with the following five-point visual scoring system: a score of 1 indicated that metastasis was definitely absent; a score of 2, probably absent; a score of 3, equivocal; a score of 4, probably present; and a score of 5, definitely present. The final determination of M stage on a per-patient basis was made by consensus of the two readers, and sites of metastases were recorded. Reading time of each MR study by each of the readers was recorded. This time was measured from the start of interpretation of images by using the picture archiving and communication system until the recording of whether a metastatic lesion was present or absent at a given site was finished.

To compare the diagnostic capability of whole-body MR imaging with and that without DW imaging with integrated FDG PET/CT for M-stage assessment, all FDG PET/CT studies were prospectively and independently interpreted by two nuclear medicine physicians with 4 and 8 years of experience, respectively (Y. Onishi and M.N.). Both readers were blinded to all information about the results of whole-body MR and conventional radiologic examinations. The presence or absence of metastases in the head and neck, thorax, abdomen and pelvis, and bone was assessed independently by the same readers. The probability of the presence of metastases on a per-patient basis was then evaluated with the same five-point visual scoring system used for whole-body MR imaging. The final determination of M stage on a per-patient basis was made by consensus of the two readers, and sites of metastases were recorded. Reading time of each FDG PET/CT study by each of the readers was recorded, which was measured from the start of interpretation of images by using the picture archiving and communication system until the recording of whether a metastatic lesion was present or absent at a given site was finished.

Statistical Analysis
A {kappa} statistic was used to determine the interobserver agreement for whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and integrated FDG PET/CT on a per-patient basis. Because the P values were exploratory in nature, no Bonferroni correction was made. Interobserver agreement was considered to be slight when {kappa} was less than 0.21, fair when {kappa} ranged from 0.21 to 0.40, moderate when {kappa} ranged from 0.41 to 0.60, substantial when {kappa} ranged from 0.61 to 0.80, and almost perfect when {kappa} ranged from 0.81 to 1.00 (31).

To compare the relative convenience of a given modality for diagnosis, the recorded reading times for both readers for each examination were averaged to determine the mean reading time of each examination per subject. The mean reading times for M-stage assessment were then compared among whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and integrated FDG PET/CT by using analysis of variance followed by Tukey honestly significant difference multiple comparison testing.

To determine the feasible threshold value and capability for M-stage assessment with the inclusion of brain metastases, receiver operating characteristic (ROC) analysis was used to compare the diagnostic capability of whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and integrated FDG PET/CT on a per-patient basis. This was followed by a statistical comparison of sensitivity, specificity, and accuracy by means of the McNemar test.

To determine the feasible threshold value and capability for M-stage assessment with the exclusion of brain metastases, ROC analysis was used to compare the diagnostic capability of the four methods on a per-patient basis. This was followed by a statistical comparison of sensitivity, specificity, and accuracy by means of the McNemar test.

A P value less than .05 was considered to indicate a statistically significant difference for all analyses.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
All whole-body MR and FDG PET/CT examinations were completed successfully without any adverse effects for any of the radiologic examinations. Representative cases are shown in Figures 1 and 2.


Figure 1A
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  		Figure 1a: Images in 74-year-old man with adenocarcinoma, lung metastases, and bone metastases. (a) Whole-body DW image (5759/70/180) in coronal plane shows bone metastases with a score of 5 as high signal intensity (arrows). However, normal spinal cord also shows high signal intensity (arrowhead) and received a score of 5. Lung metastases within both lungs could not be detected, and areas containing these metastases were scored as 1. Although this was a true-positive case, there were two false-negative sites and a false-positive site. (b) STIR turbo spin-echo MR image (3200/60/150) in coronal plane shows lung metastases (small arrows) and bone metastases (large arrows) as high signal intensity, scored as 4 and 5, respectively. This was diagnosed as a true-positive case at whole-body MR imaging with and that without DW imaging. (c) Integrated FDG PET/CT images demonstrate bilateral lung metastases (arrowheads) and bone metastases (arrows), both of which were scored as 5. This was diagnosed as a true-positive case at integrated FDG PET/CT. Color bar = standardized uptake value, gray bar = Hounsfield units.

 

Figure 1B
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  		Figure 1b: Images in 74-year-old man with adenocarcinoma, lung metastases, and bone metastases. (a) Whole-body DW image (5759/70/180) in coronal plane shows bone metastases with a score of 5 as high signal intensity (arrows). However, normal spinal cord also shows high signal intensity (arrowhead) and received a score of 5. Lung metastases within both lungs could not be detected, and areas containing these metastases were scored as 1. Although this was a true-positive case, there were two false-negative sites and a false-positive site. (b) STIR turbo spin-echo MR image (3200/60/150) in coronal plane shows lung metastases (small arrows) and bone metastases (large arrows) as high signal intensity, scored as 4 and 5, respectively. This was diagnosed as a true-positive case at whole-body MR imaging with and that without DW imaging. (c) Integrated FDG PET/CT images demonstrate bilateral lung metastases (arrowheads) and bone metastases (arrows), both of which were scored as 5. This was diagnosed as a true-positive case at integrated FDG PET/CT. Color bar = standardized uptake value, gray bar = Hounsfield units.

 

Figure 1C
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  		Figure 1c: Images in 74-year-old man with adenocarcinoma, lung metastases, and bone metastases. (a) Whole-body DW image (5759/70/180) in coronal plane shows bone metastases with a score of 5 as high signal intensity (arrows). However, normal spinal cord also shows high signal intensity (arrowhead) and received a score of 5. Lung metastases within both lungs could not be detected, and areas containing these metastases were scored as 1. Although this was a true-positive case, there were two false-negative sites and a false-positive site. (b) STIR turbo spin-echo MR image (3200/60/150) in coronal plane shows lung metastases (small arrows) and bone metastases (large arrows) as high signal intensity, scored as 4 and 5, respectively. This was diagnosed as a true-positive case at whole-body MR imaging with and that without DW imaging. (c) Integrated FDG PET/CT images demonstrate bilateral lung metastases (arrowheads) and bone metastases (arrows), both of which were scored as 5. This was diagnosed as a true-positive case at integrated FDG PET/CT. Color bar = standardized uptake value, gray bar = Hounsfield units.

 

Figure 2
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  		Figure 2: Images in 77-year-old man with adenocarcinoma and brain metastasis. Left: Whole-body DW image (5759/70/180) in coronal plane equivocally demonstrates brain metastasis, which was scored as 3, with slight high signal intensity (arrow). Right: Contrast-enhanced T1-weighted in-phase MR image (100/4.6; flip angle, 75°) in coronal plane shows brain metastasis (arrow), which was scored as 5. This was diagnosed as a false-negative case at whole-body DW imaging and as a true-positive case at whole-body MR imaging with and that without DW imaging.

 
Details of patient characteristics are shown in Table 1. Of the 203 patients, 91 had stage I disease, 33 had stage II disease, 39 had stage III disease, and 40 had stage IV disease. Of the patients with stage IV disease, 11 patients had only bone metastases, seven patients had only lung metastases, six patients had only brain metastases, four patients had only lymph node metastases, four patients had only adrenal gland metastases, and four patients had only liver metastases, while two patients had lung, bone, and adrenal gland metastases, one patient had lung and bone metastases, and one patient had liver and abdominal lymph node metastases. Moreover, 93 sites with metastases were detected among the 203 patients with NSCLC, comprising bone metastases (n = 29), lung metastases (n = 26), lymph node metastases (n = 13), brain metastases (n = 9), adrenal gland metastases (n = 8), and liver metastases (n = 8). In addition, 156 cases with other findings were identified, including renal cysts (n = 37), spondylosis (n = 25), benign pulmonary nodules except primary lesions and lung metastases (n = 25), liver cysts (n = 22), hemangiomas in the vertebrae (n = 13) and liver (n = 11), adrenal gland adenomas (n = 7), compression fractures of the vertebrae (n = 6), pancreatic cysts (n = 4), colon polyps (n = 3), normal cervical lymph nodes showing as high-signal-intensity areas on DW images (n = 2), and colon cancer (n = 1).


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  		Table 1. Patient Characteristics

 
Table 2 shows the results on a per-patient basis of the overall scores for assessment of probability of the presence of metastases recorded by the two readers on the basis of whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and FDG PET/CT. The assessments demonstrated that interobserver agreements were substantial.


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  		Table 2. Overall Interobserver Agreement on Metastatic Probability Scores on a Per-Patient Basis for Whole-Body DW Imaging, Whole-Body MR Imaging with and That without DW Imaging, and FDG-PET/CT

 
Results of comparisons of mean reading times for the four methods are shown in Figure 3. Results of analysis of variance revealed a significant difference among the mean reading times of the four methods (F = 108.1, P < .001). Mean reading times for M-stage assessment on whole-body DW images (382.4 seconds ± 177.4 [standard deviation]) and whole-body MR images obtained without DW imaging (615.6 seconds ± 284.3) were significantly shorter than those on whole-body MR images obtained with DW imaging (916.8 seconds ± 426.8, P < .05) and integrated FDG PET/CT images (881.6 seconds ± 419.9, P < .05).


Figure 3
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  		Figure 3: Graph of mean reading times for whole-body DW imaging (DWI), whole-body MR imaging with and that without DW imaging, and integrated FDG PET/CT. Mean reading times for M-stage assessment on whole-body DW images (382.4 seconds ± 177.4) and MR images obtained without DW imaging (615.6 seconds ± 284.3) were significantly shorter than those for whole-body MR images obtained with DW imaging (916.8 seconds ± 426.8, P < .05) and integrated FDG PET/CT images (881.6 seconds ± 419.9, P < .05). * = significant difference with whole-body MR imaging with DW imaging. ** = significant difference with integrated FDG PET/CT.

 
The results on a per-patient basis of ROC analyses of whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and FDG PET/CT for M-stage assessment inclusive of brain metastases are shown in Table 3 and Figure 4. The threshold value for the visual scoring system for each method was set at 4. Az values for whole-body MR imaging with DW imaging (P = .04) and integrated FDG PET/CT (P = .02) were significantly larger than that for whole-body DW imaging.


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  		Table 3. Comparison of Diagnostic Capability on a Per-Patient Basis with Inclusion of Assessment of Brain Metastases of Whole-Body DW Imaging, Whole-Body MR Imaging with and That without DW Imaging, and Integrated FDG PET/CT

 

Figure 4
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  		Figure 4: Graph of ROC analyses of whole-body DW imaging ({circ}), whole-body MR imaging with ({blacksquare}) and that without DW imaging ({square}), and integrated FDG PET/CT (bullet) for M-stage assessment inclusive of brain metastases on a per-patient basis in patients with NSCLC shows Az for whole-body MR imaging with DW imaging (P = .04) and integrated FDG PET/CT (P = .02) as significantly larger than that for whole-body DW imaging.

 
Tables 3 and 4 also show the results on a per-patient basis of a comparative analysis of the diagnostic capability, including assessment of brain metastases, of whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and integrated FDG PET/CT; lists of false-positive and false-negative cases for the M-stage assessment in patients with NSCLC identified by means of all four methods are included. When brain metastases were included, specificity and accuracy of whole-body MR imaging with (specificity, P = .02; accuracy, P < .01) and that without DW imaging (specificity, P = .02; accuracy, P = .01) and integrated FDG PET/CT (specificity, P < .01; accuracy, P < .01) were significantly higher than those of whole-body DW imaging. With regard to false-positive and false-negative lesions, cases differed from lesion to lesion as well as from patient to patient.


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  		Table 4. False-Positive and False-Negative Cases Determined on a Per-Patient Basis with Whole-Body DW Imaging, Whole-Body MR Imaging with and That without DW Imaging, and Integrated FDG PET/CT

 
The results on a per-patient basis of ROC analyses of whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and FDG PET/CT for M-stage assessment exclusive of brain metastases are shown in Table 5 and Figure 5. The threshold value for the visual scoring system for each of the methods was set at 4. Az for integrated FDG PET/CT was significantly larger than that for whole-body MR imaging without DW imaging (P = .03).


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  		Table 5. Comparison of Diagnostic Capability on a Per-Patient Basis with Exclusion of Assessment of Brain Metastases of Whole-Body DW Imaging, Whole-Body MR Imaging with and That without DW Imaging, and Integrated FDG PET/CT

 

Figure 5
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  		Figure 5: Graph of ROC analyses of whole-body DW imaging ({circ}), whole-body MR imaging with ({blacksquare}) and that without DW imaging ({square}), and integrated FDG PET/CT (bullet) for M-stage assessment exclusive of brain metastases on a per-patient basis in patients with NSCLC shows Az for integrated FDG PET/CT as significantly larger than that for whole-body MR imaging without DW imaging (P = .03).

 
The results of a comparative analysis on a per-patient basis of the diagnostic capability, with the exclusion of brain metastasis assessment, of whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and integrated FDG PET/CT are also shown in Table 5. Specificity and accuracy of whole-body MR imaging with DW imaging (specificity, P = .02; accuracy, P = .02) and integrated FDG PET/CT (specificity, P < .01; accuracy, P < .01) were significantly higher than those of whole-body DW imaging. Specificity of whole-body MR imaging without DW imaging was significantly higher than that of whole-body DW imaging (P = .02). Accuracy of integrated FDG PET/CT was significantly higher than that of whole-body MR imaging without DW imaging (P < .01).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 
Our results demonstrate that whole-body MR imaging with DW imaging can be used for M-stage assessment in patients with NSCLC with accuracy as good as that of integrated PET/CT. In addition, when whole-body DW imaging is adopted as an adjunct of whole-body MR examination, the diagnostic capability of whole-body MR examination for M-stage assessment can be enhanced, especially when evaluation of brain metastases at whole-body MR imaging is not included. After tissue diagnosis of NSCLC has been established, attention should be focused on the determination of the extent of disease, or stage. M-stage assessment is therefore important for determining the appropriate management of this disease, and integrated and/or coregistered FDG PET/CT or PET is currently in wide use.

A comparison of interobserver agreement and mean reading time for all four methods showed that interobserver agreements were almost the same and substantial on a per-patient basis. In addition, mean reading time for whole-body MR imaging with DW imaging was not significantly different from that of integrated FDG PET/CT, while mean reading times for whole-body DW imaging and whole-body MR imaging without DW imaging were significantly shorter than those for whole-body MR imaging with DW imaging and integrated PET/CT. Therefore, whole-body MR examination as a conventional screening tool for M-stage assessment in patients with NSCLC may be considered as equivalent to integrated FDG PET/CT in terms of interobserver agreement and time required.

Our results of a comparison of capability for M-stage assessment with the inclusion of brain metastases showed that Az for whole-body DW imaging was significantly smaller than that for whole-body MR imaging with DW imaging and integrated FDG PET/CT. In addition, specificity and accuracy of whole-body DW imaging were significantly lower than those of whole-body MR imaging with and that without DW imaging and integrated FDG PET/CT. These findings suggest that whole-body DW imaging should be considered a less specific and accurate diagnostic tool than integrated FDG PET/CT for M-stage assessment in patients with NSCLC. In addition, although false-positive and false-negative cases differed from lesion to lesion and from patient to patient, lung metastases and pulmonary abnormalities and/or brain metastases accounted for the majority of false-positive and/or false-negative lesions identified with any of the four methods.

Results of previously published studies by many investigators have suggested no MR examinations of any type could have a capability for nodule detection similar to that of CT. In addition, integrated FDG PET/CT data obtained with FDG PET with free-breathing conditions, as well as data obtained with CT alone, have indicated their inferior capability for nodule detection compared with that of routine CT examination with breath holding at end inspiration (32,33). Our results are therefore compatible with these previously published results. In addition, with consideration of their capability for detection of brain metastases, detection of small metastases with whole-body DW imaging and integrated FDG PET/CT may be difficult because of the lower contrast ratio between normal cortex and brain metastases than that obtainable with contrast-enhanced MR imaging and because of the extremely high level of physiologic tissue accumulation of FDG in the cerebral cortex (20,34,35). Because there seems to be no significant difference in diagnostic accuracy among whole-body MR imaging with and that without DW imaging and integrated FDG PET/CT and in the diagnosis of false-positive and false-negative lesions and cases, whole-body MR imaging with and that without DW imaging can be considered as effective as integrated FDG PET/CT for M-stage assessment with the inclusion of brain metastases.

In view of the aforementioned difficulties at FDG PET or PET/CT for assessment of brain metastases (20,34,35), the guidelines for assessment of TNM staging in NSCLC recommend that contrast-enhanced CT or MR imaging should be used instead of FDG PET or FDG PET/CT for assessment of brain metastases in routine clinical practice. Direct comparison of the diagnostic accuracy for M-stage assessment with the exclusion of brain metastases of all four methods is important for determination of the actual utility of whole-body MR examination. The results of our comparison of the diagnostic capability for M-stage assessment with the exclusion of brain metastases showed that Az for whole-body MR imaging without DW imaging was significantly smaller than that for integrated FDG PET/CT. However, although the diagnostic performance of whole-body DW imaging for M-stage assessment—regardless of whether brain metastases are excluded or not—was lower than that of integrated FDG PET/CT, adoption of whole-body DW imaging as one of the sequences of whole-body MR examination can enhance the diagnostic accuracy of whole-body MR imaging, so that it is no longer significantly different from that of integrated FDG PET/CT. These findings indicate that whole-body DW imaging may be used to direct radiologists' attention to areas of suspected metastases but not for distinguishing malignant from benign lesions by using visual assessment of signal intensity, as was previously reported for apparent diffusion coefficient (36,37). In addition, whole-body MR imaging with DW imaging can be considered as effective for M-stage assessment as integrated FDG PET/CT, provided that brain metastases are excluded.

This study had certain limitations. First, previous studies have indicated that when a lung cancer reaches 5 mm in diameter, it has undergone approximately 20 doublings and contains about 100 million cells (38), while angiogenesis occurs in most tumors with a diameter of 1–2 mm (39,40). These findings suggest that we may have missed some suspect metastatic sites that could not be detected with any of the four methods. Second, although we ensured that the final M-stage and metastasis of a given site were decided by consensus—based on the results of standard imaging; pathologic results from endoscopic, CT-guided, or surgical biopsies; and results of follow-up examinations performed for more than 12 months—at a conference attended by radiologists, radiation oncologists, pathologists, oncologists, and surgeons with more than 10 years of experience, the final M stage and metastasis of a given site could not be diagnosed in every patient at pathologic examination; some sensitivity and specificity results of our study may have been biased because of incomplete pathologic sampling. However, these limitations might bias estimates of the absolute accuracy of whole-body MR and integrated FDG PET/CT examinations, and one might expect these biases to affect both modalities relatively equally. Therefore, the difference between the modalities may be less affected by such bias.

Third, to implement whole-body MR imaging in routine clinical practice, development of a workstation and performance of further investigations for the determination of feasible sequences for whole-body MR imaging on a per-site basis may be warranted. In addition, standardization of sequences for M-stage assessment by using whole-body MR imaging with DW imaging and improvement of MR systems for whole-body examination are necessary to adopt this method for routine clinical practice and to substitute it for integrated FDG PET/CT.

Fourth, although interobserver agreement, mean reading time, and diagnostic capability for initial M-stage assessment were compared among whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and integrated FDG PET/CT, those of the above-mentioned four methods were not compared with those of each or combined standard radiologic examination. Results of a few studies (41–43) suggest that integrated PET/CT should be considered as having diagnostic accuracy equal to or higher than that of conventional radiologic imaging or PET alone in other malignancies. In addition, these study results also suggest the limitation of integrated PET/CT and the way for using it together with conventional radiologic imaging in these malignancies. Therefore, direct comparison among the above-mentioned four methods and standard radiologic examinations may also be warranted to determine the real clinical importance of whole-body MR imaging with DW imaging and integrated FDG PET/CT for M-stage assessment in patients with NSCLC. We will plan a study in the near future to prospectively and directly compare clinical utility for M-stage assessment in patients with NSCLC among whole-body MR imaging, integrated FDG PET/CT, standard radiologic examinations, and combinations of techniques discussed in this article in a large prospective cohort.

In conclusion, whole-body MR imaging with DW imaging can be used for M-stage assessment in patients with NSCLC with accuracy as good as that of integrated PET/CT; in addition, when whole-body DW imaging is adopted as an adjunct for whole-body MR imaging without whole-body DW imaging, the diagnostic accuracy of whole-body MR examination can be improved.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
IMPLICATIONS FOR PATIENT CARE
 References
 


   IMPLICATIONS FOR PATIENT CARE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
References
 


   ACKNOWLEDGMENTS
 
The authors thank Yoshiyuki Ohno, MD, PhD, MPH, Professor Emeritus, Nagoya University (Department of Preventive Medicine, Graduate School of Medicine); Yoshimasa Maniwa, MD (Division of Cardiovascular, Thoracic and Pediatric Surgery, Kobe University Graduate School of Medicine); and Yoshihiro Nishimura, MD (Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine) for their contribution to this study.


   FOOTNOTES
 

Abbreviations: Az = area under ROC curve • DW = diffusion-weighted • FDG = fluorine 18 fluorodeoxyglucose • NSCLC = non–small cell lung cancer • ROC = receiver operating characteristic • STIR = short inversion time inversion recovery

See also the article by Yi et al in this issue.

Author contributions: Guarantors of integrity of entire study, Y. Ohno, K.S.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, Y. Ohno; clinical studies, Y. Ohno, H.K., Y. Onishi, D.T., M.N., T.Y., Y.K., K.S.; statistical analysis, Y. Ohno, S.M.; and manuscript editing, Y. Ohno, S.M., K.S.

See Materials and Methods for pertinent disclosures.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 IMPLICATIONS FOR PATIENT CARE
 References
 

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