Published online before print October 22, 2007, 10.1148/radiol.2453061889
(Radiology 2007;245:824-830.)
© RSNA, 2007
Blood Vessel Morphologic Changes Depicted with MR Angiography during Treatment of Brain Metastases: A Feasibility Study1
Elizabeth Bullitt, MD,
Nancy U. Lin, MD,
J. Keith Smith, MD, PhD,
Donglin Zeng, PhD,
Eric P. Winer, MD,
Lisa A. Carey, MD,
Weili Lin, PhD, and
Matthew G. Ewend, MD
1 From the Computer Assisted Surgery and Imaging Laboratory, University of North Carolina, 247 Wing E, CB 7062, Chapel Hill, NC, 27599 (E.B., J.K.S., D.Z., L.A.C., W.L., M.G.E.); and Department of Radiology, Dana-Farber/Harvard Cancer Center, Boston, Mass (N.U.L., E.P.W.). Received November 4, 2006; revision requested January 10, 2007; revision received January 30; accepted March 16; final version accepted April 16. Supported in part by the National Institute of Biomedical Imaging and Bioengineering (R01EB000219), Avon Foundation (P50CA89393-AV-55P and P50CA58185-AV-55P2), National Cancer Institute (P30CA16086-29S1, P50CA089393-05S1, and P30CA58223), National Institutes of Health (M01RR00046), and American Society of Clinical Oncology Young Investigator Award.
Address correspondence to E.B. (e-mail: bullitt{at}med.unc.edu).
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ABSTRACT
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Purpose: To prospectively determine if magnetic resonance (MR) angiography can depict intracranial vascular morphologic changes during treatment of brain metastases from breast cancer and if serial quantitative vessel tortuosity measurements can be used to predict tumor treatment response sooner than traditional methods.
Materials and Methods: Institutional review board approval and informed consent were obtained for this HIPAA-compliant study. Twenty-two women aged 31–61 years underwent brain MR angiography prior to and 2 months after initiation of lapatinib therapy for brain metastases from breast cancer. Vessels were extracted from MR angiograms with a computer program. Changes in vessel number, radius, and tortuosity were calculated mathematically, normalized with values obtained in 34 healthy control subjects (19 women, 15 men; age range, 19–72 years), and compared with subsequent assessments of tumor volume and clinical course.
Results: All patients exhibited abnormal vessel tortuosity at baseline. Nineteen (86%) patients did not exhibit improvement in vessel tortuosity at 2-month follow-up, and all patients demonstrated tumor growth at 4-month follow-up. Vessel tortuosity measurements enabled us to correctly predict treatment failure 1–2 months earlier than did traditional methods. Three (14%) patients had quantitative improvement in vessel tortuosity at 2-month follow-up, with drop out of small abnormal vessels and straightening of large vessels. Each of the two patients for whom further follow-up data were available responded to treatment for more than 6 months.
Conclusion: Study results established the feasibility of using MR angiography to quantify vessel shape changes during therapy. Although further research is required, results suggest that changes in vessel tortuosity might enable early prediction of tumor treatment response.
© RSNA, 2007
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INTRODUCTION
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Angiogenesis, the outgrowth of new blood vessels from existing vessels, is necessary for tumors to grow larger than 1–2 mm3 (1). One investigational impediment is the lack of a noninvasive imaging method that can be used to monitor individual vessels over time (2).
Vessel tortuosity is of particular interest. Within 24 hours after injection of 20–50 cancer cells in animal models, initially healthy vessels in the tumor vicinity become abnormally tortuous (3). This abnormality extends beyond tumor boundaries and precedes vascular sprouting (3). Baish and Jain (4) aptly described the typical abnormal configuration as "many smaller bends upon each larger bend." Abnormal vascular tortuosity is associated not only with malignancy in animal models but also with a range of cancers in human patients (5–7). The cause may be related to growth factor–related changes in the vessel wall, including alteration of the basement membrane, loss of pericytes and smooth muscle, and proliferation of endothelial cells (8). In animals, cancer-associated vessel tortuosity abnormalities are known to resolve during antiangiogenic treatment (3,9,10).
The purpose of this study was to prospectively determine if magnetic resonance (MR) angiography can depict intracranial vascular morphologic changes during treatment of brain metastases from breast cancer and if serial quantitative vessel tortuosity measurements can be used to predict tumor treatment response sooner than traditional methods.
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MATERIALS AND METHODS
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Subject Groups
We evaluated images obtained in (a) a subset of patients with tumors who were enrolled in an underlying drug trial and (b) healthy control subjects. All three studies (the underlying drug trial, our tumor imaging study, and the collection of control images in healthy subjects) were compliant with the Health Insurance Portability and Accountability Act, were approved by the institutional review boards of all participating hospitals, and required signed informed consent.
Patients with tumors who were involved in our imaging study included 22 of 39 women enrolled in a multicenter phase II trial of lapatinib in the treatment of HER2-positive breast cancer metastatic to the brain. Eligibility for enrollment in the drug study included HER2-positive breast cancer, new or progressive brain metastases, and at least one lesion with a diameter of at least 1 cm. The findings of the underlying drug study were presented at a conference (11) and will be reported independently. Our imaging study included all 22 female patients (age range, 31–61 years; mean age, 52 years) who consented to enter the imaging study and for whom MR angiograms were acquired at baseline and 2-month follow-up. An interim report on the imaging study was presented at a computer science conference (12).
A database of MR angiograms obtained in 34 healthy control subjects without history of hypertension, diabetes, cancer, or neurologic or psychiatric disease was used to establish what was considered healthy. Subjects ranged in age from 19 to 72 years (mean age, 38 years; 19 women, 15 men). This database was used to derive means ± standard deviations of healthy vessel shape parameters, without age or sex matching to individual patients with tumors.
Image Acquisition and Clinical Study End Point
In the underlying clinical trial, we acquired T1- and T2-weighted MR angiograms and T1-weighted gadolinium-enhanced MR angiograms at baseline, 2-month follow-up, and every 2 months thereafter until the patient was withdrawn from the study (criteria for withdrawal will be given later). In our secondary imaging study, we obtained MR angiograms at baseline and 2-month follow-up.
Different institutions used MR units manufactured by different vendors. All institutions were required to use a standardized format to obtain MR angiograms and to perform subsequent MR angiography in the same patient with the same machine. Three-dimensional time-of-flight MR angiography covered the entire head and was performed prior to gadolinium-based contrast material injection by using multiple overlapping (25%) thin slabs and a magnetization transfer pulse for background suppression of white matter (5). Imaging parameters were as follows: voxel size, 0.5 x 0.5 x 0.8 mm; repetition time msec/echo time msec, 35/3; and flip angle, 22°. Although the base matrix was 448 x 448, a rectangular field of view of 0.786 and a partial Fourier factor of 0.8 were used to reduce the data acquisition time to 18 minutes.
Patients received care as part of the underlying drug trial until disease progressed, toxicity occurred, or consent was withdrawn. Gadolinium-enhanced MR imaging was used to define progressive brain disease as an increase of more than 20% in the sum of the longest dimensions of target lesions, an increase of at least 5 mm in the longest dimension of at least one lesion, and/or the appearance of one or more new lesions at least 6 mm in size (adapted for the brain from Response Eval uation Criteria in Solid Tumors [RECIST] [13]). The treating physician, with the assistance of clinical radiologists, judged whether progressive disease was present. Multiple site physicians (N.U.L., J.K.S., E.P.W., L.A.C., and M.G.E.) with more than 90 years of experience, collectively, in treating breast cancer were involved. Because of progressive disease or death, no patients now remain in the study.
Image Processing for Vessels
Digital images obtained in patients with tumors were sent for processing to an author (E.B.) who was not involved in patient care. This author was blinded to each patient's clinical status until image analysis was completed and findings were reported to the central clinical group. The findings were not used clinically, a fact that was understood by the patients.
Images were processed with computer programs applied by this same author. Vessels were segmented from the entire brain (14) and postprocessed to yield a connected set of vessel trees (15). Each vessel was mathematically described as an ordered list of four-dimensional vector values, in which the first three values represented an x, y, z spatial point along the vessel skeleton and the fourth value represented the associated radius (14,15). This method is used to define tubular objects that have a signal intensity higher than that of the background (14,15); thus, it is not impeded by the so-called Venetian blind effect of multiple overlapping thin slabs. Vessel tree extraction took approximately 30 minutes for each subject.
This program can be used to calculate shape measurements for vessels clipped to the region of an individual tumor (7); however, many patients in the current study had numerous metastases. It was not feasible to analyze many regions of interest. Thus, each patient's segmented vasculature was analyzed as a whole, with results for each parameter averaged over the brain.
Shape measurements were calculated automatically. Measurements included vessel number; average radius; average vessel tortuosity, as calculated with the sum of angles metric (SOAM) and the inflection count metric (ICM); and malignancy probability (MP). Vessel number is the number of individual unbranched vessels and is reported as an integer. Average radius is the sum of radii at all vessel skeleton points divided by the number of points and is measured in millimeters.
Average vessel tortuosity was measured with the SOAM and ICM techniques. The SOAM technique is used to calculate the sum of curvatures along a space curve by using successive trios of equally spaced vessel skeleton points, and it normalizes according to vessel length (16). SOAM values are elevated in the presence of high-frequency low-amplitude bends and are measured in radians per centimeter. The ICM technique is used to calculate the number of inflection points along a space curve. This number (plus 1) is then multiplied by the total path length of the curve divided by the distance between end points (16). ICM values are elevated when a curve exhibits a high-amplitude sinusoidal pattern and are reported as a dimensionless number.
The MP equation was derived from a study of multiple vessel shape parameters in patients with a variety of tumor types (7). In that study, discriminant analysis revealed that only a weighted combination of the SOAM and ICM tortuosity measurements appeared to be effective in separating benign from malignant disease. To calculate MP, the SOAM and ICM measurements are first normalized with z scores (SOAMz and ICMz, respectively) by the means and standard deviations of healthy values over the same region of interest and are then combined, as follows: X = 1.7160 · SOAMz + 0.51241 · ICMz – 2.8659 and Y = –0.24876 · SOAMz – 0.58972 · ICMz – 0.19672. The MP was then calculated with the following equation: exp(X)/[exp(X) + exp(Y)].
The calculated MP for each tumor test case will range from 0 to 1 (equivalent to 0% to 100%). Higher values indicate a higher MP. In essence, this equation provides a quantitative formulation of Baish and Jain's phrase "many smaller bends upon each larger bend" (4), with SOAM being sensitive to smaller bends and ICM being sensitive to larger bends (7).
Image Processing for Tumors
A difficulty with the unidimensional RECIST measurements used in the underlying clinical trial is that sequential estimates of tumor size may be confounded by changes in imaging section angle. Thus, as part of the research protocol, tumor volumes were calculated from gadolinium-enhanced T1-weighted images for all lesions 1 cm3 or larger by using a program that defined tumors with polygon drawing and filling on orthogonal cuts through an image volume. An author (E.B.) selected the tumors for analysis. Tumor volume was automatically calculated as the number of labeled voxels multiplied by voxel size and measured in cubic centimeters. A meaningful increase or decrease in tumor volume was predefined as a volumetric increase or decrease from the baseline value of at least 20%, with a concomitant change in volume of at least 0.5 cm3. Treatment failure based on volumetrics was predefined as growth by 20% and 0.5 cm3 of either a single lesion or the sum of all segmented lesions.
Data Analyses
The means and standard deviations of vessel number, the average radius, and the tortuosity as measured with SOAM and ICM were calculated for healthy control subjects, patients with tumors at baseline and 2-month follow-up, and subsets of patients with tumors that exhibited improvement in MP (reduction in MP by 20%) at 2-month follow-up and those with tumors that did not exhibit improvement in MP at 2-month follow-up. The means and standard deviations of MP were also calculated for patients with tumors at both time points.
We compared change in MP at 2-month follow-up with the patient's subsequent clinical course and with subsequent tumor volumetric calculations. A decrease in MP of 20% was predefined as being indicative of vascular normalization. In patients who did not exhibit improvement in MP at 2-month follow-up, the means and standard deviations of the time to treatment failure were calculated for clinical and volumetric criteria. For the three patients in whom MP decreased at 2-month follow-up, we provided clinical and volumetric information for each patient individually.
An interesting uncertainty was whether normalization of vessel tortuosity was related to drop out of small abnormal vessels, straightening of initially tortuous vessels, or both. We also hoped to determine if vessels that exhibited straightening could lie outside tumor boundaries. Thus, we examined segmented vessels and tumors by using a three-dimensional display and manually sought four examples of major named vessels that could be identified from one image to the next, had an appearance that changed over time, and lay totally or partially outside of tumor confines. Selected vessels included a pair of frontopolar arteries in one patient and both a posterior cerebral artery and a superior cerebellar artery in another patient. The display interface offered the option of clicking on an individual vessel and hiding it and its associated subtree. We did so for some images to prevent the obscuration of vessels of interest by a plethora of tiny branches. The original quantitative analysis involved the entire intracerebral vasculature. Finally, the display interface offered the option of clicking on an individual vessel to obtain a report on the morphologic findings for that vessel. We thereby examined change in radius of the four major named vessels manually selected as examples of vascular normalization.
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RESULTS
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All patients had marked vessel tortuosity abnormalities at baseline (Table). Nineteen patients exhibited no improvement in MP at 2-month follow-up. Nine of these patients had a marked increase in tumor size at analysis with both RECIST (13) and volumetric criteria at 2-month follow-up, and they were immediately withdrawn from the study. The remaining 10 patients exhibited stability or a decrease in tumor volume at 2-month follow-up. This finding indicated at least transient drug response. However, T1-weighted images obtained in these potentially responsive patients showed volumetric tumor growth at 4-month follow-up and steady tumor growth thereafter. The mean time required to recognize treatment failure was 3.9 months + 1.6 with clinical criteria, 3.1 months + 1.4 with volumetric measurement, and 2.0 months + 0.0 with vessel shape analysis.
Reduction in MP
Three patients had reduced MP at 2-month follow-up. Patient R1 (Fig 1) had one large tumor. Her MP decreased from 100% to 64% at 2-month follow-up, concomitant with a 61% reduction in tumor volume (from 18.4 cm3 to 7.2 cm3). Her tumor continued to regress, exhibiting an 85% volume reduction (from 18.4 cm3 to 2.7 cm3) at 4-month follow-up, with stability thereafter. This patient exhibited the longest clinical remission of any patient in the study; however, her disease eventually showed signs of central nervous system progression, and she was removed from the study after 11 months because she developed carcinomatous meningitis.
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Figure 1a: Normalization of vessel shape during treatment. (a, b) Transverse gadolinium-enhanced T1-weighted MR images (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38, 0.9 x 0.9-mm in-plane spatial resolution, 3-mm intersection spacing) through the center of a tumor (arrow) at baseline (a) and 2-month follow-up (b). Note the reduction in tumor size in b. (c) Three-dimensional rendering of intracerebral vessels and of the patient's segmented tumor (gray area) from a lateral point of view (nose to left) at baseline. Vessels are color coded according to circulatory group. Blue = right carotid and right middle cerebral circulation, cyan = left carotid and left middle cerebral circulation, gold = posterior cerebral circulation, red = anterior cerebral circulation. (d) Three-dimensional rendering of vessels at baseline similar to c but with tumor visualization turned off. White rectangle indicates the region magnified in e. This region extends outside tumor margins. (e) Magnified region of frontopolar arteries at baseline. Note the markedly abnormally tortuous left frontopolar artery (arrows). The right frontopolar artery courses parallel to and just above the left frontopolar artery from this point of view, and it appears dilated. Multiple medium and small vessel branches in the vicinity are abnormally tortuous. (f) Three-dimensional rendering of the intracerebral vessels at 2-month follow-up from the same point of view as c–e. White rectangle indicates the region magnified in g. (g) Magnification of the region of the frontopolar arteries at 2-month follow-up. Note the straightening of the left frontopolar artery, the reduction in radius of the right frontopolar artery, the straightening of medium-sized branches, and the loss of small abnormal vessels—as compared with the magnification of the baseline vessels shown in e.
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Figure 1b: Normalization of vessel shape during treatment. (a, b) Transverse gadolinium-enhanced T1-weighted MR images (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38, 0.9 x 0.9-mm in-plane spatial resolution, 3-mm intersection spacing) through the center of a tumor (arrow) at baseline (a) and 2-month follow-up (b). Note the reduction in tumor size in b. (c) Three-dimensional rendering of intracerebral vessels and of the patient's segmented tumor (gray area) from a lateral point of view (nose to left) at baseline. Vessels are color coded according to circulatory group. Blue = right carotid and right middle cerebral circulation, cyan = left carotid and left middle cerebral circulation, gold = posterior cerebral circulation, red = anterior cerebral circulation. (d) Three-dimensional rendering of vessels at baseline similar to c but with tumor visualization turned off. White rectangle indicates the region magnified in e. This region extends outside tumor margins. (e) Magnified region of frontopolar arteries at baseline. Note the markedly abnormally tortuous left frontopolar artery (arrows). The right frontopolar artery courses parallel to and just above the left frontopolar artery from this point of view, and it appears dilated. Multiple medium and small vessel branches in the vicinity are abnormally tortuous. (f) Three-dimensional rendering of the intracerebral vessels at 2-month follow-up from the same point of view as c–e. White rectangle indicates the region magnified in g. (g) Magnification of the region of the frontopolar arteries at 2-month follow-up. Note the straightening of the left frontopolar artery, the reduction in radius of the right frontopolar artery, the straightening of medium-sized branches, and the loss of small abnormal vessels—as compared with the magnification of the baseline vessels shown in e.
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Figure 1c: Normalization of vessel shape during treatment. (a, b) Transverse gadolinium-enhanced T1-weighted MR images (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38, 0.9 x 0.9-mm in-plane spatial resolution, 3-mm intersection spacing) through the center of a tumor (arrow) at baseline (a) and 2-month follow-up (b). Note the reduction in tumor size in b. (c) Three-dimensional rendering of intracerebral vessels and of the patient's segmented tumor (gray area) from a lateral point of view (nose to left) at baseline. Vessels are color coded according to circulatory group. Blue = right carotid and right middle cerebral circulation, cyan = left carotid and left middle cerebral circulation, gold = posterior cerebral circulation, red = anterior cerebral circulation. (d) Three-dimensional rendering of vessels at baseline similar to c but with tumor visualization turned off. White rectangle indicates the region magnified in e. This region extends outside tumor margins. (e) Magnified region of frontopolar arteries at baseline. Note the markedly abnormally tortuous left frontopolar artery (arrows). The right frontopolar artery courses parallel to and just above the left frontopolar artery from this point of view, and it appears dilated. Multiple medium and small vessel branches in the vicinity are abnormally tortuous. (f) Three-dimensional rendering of the intracerebral vessels at 2-month follow-up from the same point of view as c–e. White rectangle indicates the region magnified in g. (g) Magnification of the region of the frontopolar arteries at 2-month follow-up. Note the straightening of the left frontopolar artery, the reduction in radius of the right frontopolar artery, the straightening of medium-sized branches, and the loss of small abnormal vessels—as compared with the magnification of the baseline vessels shown in e.
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Figure 1d: Normalization of vessel shape during treatment. (a, b) Transverse gadolinium-enhanced T1-weighted MR images (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38, 0.9 x 0.9-mm in-plane spatial resolution, 3-mm intersection spacing) through the center of a tumor (arrow) at baseline (a) and 2-month follow-up (b). Note the reduction in tumor size in b. (c) Three-dimensional rendering of intracerebral vessels and of the patient's segmented tumor (gray area) from a lateral point of view (nose to left) at baseline. Vessels are color coded according to circulatory group. Blue = right carotid and right middle cerebral circulation, cyan = left carotid and left middle cerebral circulation, gold = posterior cerebral circulation, red = anterior cerebral circulation. (d) Three-dimensional rendering of vessels at baseline similar to c but with tumor visualization turned off. White rectangle indicates the region magnified in e. This region extends outside tumor margins. (e) Magnified region of frontopolar arteries at baseline. Note the markedly abnormally tortuous left frontopolar artery (arrows). The right frontopolar artery courses parallel to and just above the left frontopolar artery from this point of view, and it appears dilated. Multiple medium and small vessel branches in the vicinity are abnormally tortuous. (f) Three-dimensional rendering of the intracerebral vessels at 2-month follow-up from the same point of view as c–e. White rectangle indicates the region magnified in g. (g) Magnification of the region of the frontopolar arteries at 2-month follow-up. Note the straightening of the left frontopolar artery, the reduction in radius of the right frontopolar artery, the straightening of medium-sized branches, and the loss of small abnormal vessels—as compared with the magnification of the baseline vessels shown in e.
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Figure 1e: Normalization of vessel shape during treatment. (a, b) Transverse gadolinium-enhanced T1-weighted MR images (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38, 0.9 x 0.9-mm in-plane spatial resolution, 3-mm intersection spacing) through the center of a tumor (arrow) at baseline (a) and 2-month follow-up (b). Note the reduction in tumor size in b. (c) Three-dimensional rendering of intracerebral vessels and of the patient's segmented tumor (gray area) from a lateral point of view (nose to left) at baseline. Vessels are color coded according to circulatory group. Blue = right carotid and right middle cerebral circulation, cyan = left carotid and left middle cerebral circulation, gold = posterior cerebral circulation, red = anterior cerebral circulation. (d) Three-dimensional rendering of vessels at baseline similar to c but with tumor visualization turned off. White rectangle indicates the region magnified in e. This region extends outside tumor margins. (e) Magnified region of frontopolar arteries at baseline. Note the markedly abnormally tortuous left frontopolar artery (arrows). The right frontopolar artery courses parallel to and just above the left frontopolar artery from this point of view, and it appears dilated. Multiple medium and small vessel branches in the vicinity are abnormally tortuous. (f) Three-dimensional rendering of the intracerebral vessels at 2-month follow-up from the same point of view as c–e. White rectangle indicates the region magnified in g. (g) Magnification of the region of the frontopolar arteries at 2-month follow-up. Note the straightening of the left frontopolar artery, the reduction in radius of the right frontopolar artery, the straightening of medium-sized branches, and the loss of small abnormal vessels—as compared with the magnification of the baseline vessels shown in e.
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Figure 1f: Normalization of vessel shape during treatment. (a, b) Transverse gadolinium-enhanced T1-weighted MR images (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38, 0.9 x 0.9-mm in-plane spatial resolution, 3-mm intersection spacing) through the center of a tumor (arrow) at baseline (a) and 2-month follow-up (b). Note the reduction in tumor size in b. (c) Three-dimensional rendering of intracerebral vessels and of the patient's segmented tumor (gray area) from a lateral point of view (nose to left) at baseline. Vessels are color coded according to circulatory group. Blue = right carotid and right middle cerebral circulation, cyan = left carotid and left middle cerebral circulation, gold = posterior cerebral circulation, red = anterior cerebral circulation. (d) Three-dimensional rendering of vessels at baseline similar to c but with tumor visualization turned off. White rectangle indicates the region magnified in e. This region extends outside tumor margins. (e) Magnified region of frontopolar arteries at baseline. Note the markedly abnormally tortuous left frontopolar artery (arrows). The right frontopolar artery courses parallel to and just above the left frontopolar artery from this point of view, and it appears dilated. Multiple medium and small vessel branches in the vicinity are abnormally tortuous. (f) Three-dimensional rendering of the intracerebral vessels at 2-month follow-up from the same point of view as c–e. White rectangle indicates the region magnified in g. (g) Magnification of the region of the frontopolar arteries at 2-month follow-up. Note the straightening of the left frontopolar artery, the reduction in radius of the right frontopolar artery, the straightening of medium-sized branches, and the loss of small abnormal vessels—as compared with the magnification of the baseline vessels shown in e.
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Figure 1g: Normalization of vessel shape during treatment. (a, b) Transverse gadolinium-enhanced T1-weighted MR images (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38, 0.9 x 0.9-mm in-plane spatial resolution, 3-mm intersection spacing) through the center of a tumor (arrow) at baseline (a) and 2-month follow-up (b). Note the reduction in tumor size in b. (c) Three-dimensional rendering of intracerebral vessels and of the patient's segmented tumor (gray area) from a lateral point of view (nose to left) at baseline. Vessels are color coded according to circulatory group. Blue = right carotid and right middle cerebral circulation, cyan = left carotid and left middle cerebral circulation, gold = posterior cerebral circulation, red = anterior cerebral circulation. (d) Three-dimensional rendering of vessels at baseline similar to c but with tumor visualization turned off. White rectangle indicates the region magnified in e. This region extends outside tumor margins. (e) Magnified region of frontopolar arteries at baseline. Note the markedly abnormally tortuous left frontopolar artery (arrows). The right frontopolar artery courses parallel to and just above the left frontopolar artery from this point of view, and it appears dilated. Multiple medium and small vessel branches in the vicinity are abnormally tortuous. (f) Three-dimensional rendering of the intracerebral vessels at 2-month follow-up from the same point of view as c–e. White rectangle indicates the region magnified in g. (g) Magnification of the region of the frontopolar arteries at 2-month follow-up. Note the straightening of the left frontopolar artery, the reduction in radius of the right frontopolar artery, the straightening of medium-sized branches, and the loss of small abnormal vessels—as compared with the magnification of the baseline vessels shown in e.
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Patient R2 (Fig 2) had multiple posterior fossa lesions. Her MP decreased from 100% to 4% at 2-month follow-up, with stability of lesion size volumetrically (from 14.3 cm3 to 13.7 cm3, 4% volume reduction). She died unexpectedly of an unknown cause, and no autopsy was performed. No evidence of tumor progression was found at the time of her last staging study. No further information was available.
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Figure 2a: Normalization of vessel shape during treatment. (a) Transverse gadolinium-enhanced T1-weighted MR image (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38) at baseline shows multiple cerebellar tumors. (b) Three-dimensional rendering of the segmented tumors (gray area) and basilar, left superior cerebellar, and left posterior cerebral arteries at baseline, as shown from a lateral point of view. Note the abnormal tortuosity of the left superior cerebellar artery (arrows). The posterior cerebral artery is also abnormal, albeit to a lesser degree. (c) Three-dimensional rendering of the same vessels from the same point of view as in b at 2-month follow-up. Note the arterial straightening.
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Figure 2b: Normalization of vessel shape during treatment. (a) Transverse gadolinium-enhanced T1-weighted MR image (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38) at baseline shows multiple cerebellar tumors. (b) Three-dimensional rendering of the segmented tumors (gray area) and basilar, left superior cerebellar, and left posterior cerebral arteries at baseline, as shown from a lateral point of view. Note the abnormal tortuosity of the left superior cerebellar artery (arrows). The posterior cerebral artery is also abnormal, albeit to a lesser degree. (c) Three-dimensional rendering of the same vessels from the same point of view as in b at 2-month follow-up. Note the arterial straightening.
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Figure 2c: Normalization of vessel shape during treatment. (a) Transverse gadolinium-enhanced T1-weighted MR image (magnetization-prepared rapid acquisition gradient-echo sequence, 1700/4.38) at baseline shows multiple cerebellar tumors. (b) Three-dimensional rendering of the segmented tumors (gray area) and basilar, left superior cerebellar, and left posterior cerebral arteries at baseline, as shown from a lateral point of view. Note the abnormal tortuosity of the left superior cerebellar artery (arrows). The posterior cerebral artery is also abnormal, albeit to a lesser degree. (c) Three-dimensional rendering of the same vessels from the same point of view as in b at 2-month follow-up. Note the arterial straightening.
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Patient R3 (Fig 3) had multiple tumors in the posterior fossa. Her MP decreased from 62% to 18% at 2-month follow-up, albeit with concomitant enlargement of her tumor burden volumetrically (30%, from 3.7 cm3 to 4.8 cm3). RECIST criteria (13) could not be used to detect this volumetric change, and she remained in the study, per the clinical protocol. Her tumors stopped growing thereafter and remained volumetrically stable through 6-month follow-up, at which time she was removed from the study because of late recognition with use of RECIST criteria (13) that her tumors had grown from baseline. However, all tumors were volumetrically stable during months 2–6. It is unknown how much longer her tumor volume might have remained stable with treatment.
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Figure 3: Three-dimensional rendering shows loss of small abnormal vessels during treatment. Left image shows left middle cerebral circulation at baseline and is rendered from a lateral point of view. Arrows point to clusters of small abnormal vessels that were not seen at 2-month follow-up. Right image was rendered from a similar point of view at 2-month follow-up.
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Mean progression-free survival as assessed with clinical criteria was 8.5 months + 3.5 in the two patients who exhibited decreased MP at 2-month follow-up and for whom longer-term data were available and 3.9 months + 1.6 in the 19 patients without normalization of vessel shape.
Normalization of Vessel Shape
By definition, a decrease in an initially elevated MP indicates normalization of vessel tortuosity abnormalities. This normalization occurred because of loss of small tortuous vessels and discernible straightening of larger arteries. Change in vessel radius also occurred during treatment in all four of the major named vessels that were analyzed. The radii of the paired frontopolar arteries were asymmetric at baseline (0.41 mm and 0.66 mm for the highly tortuous left and right frontopolar arteries, respectively) but became more symmetric at 2-month follow-up (0.42 mm and 0.45 mm for the highly tortuous left and right frontopolar arteries, respectively). The radii of the posterior cerebral and superior cerebellar arteries decreased (from 0.88 cm to 0.64 cm and from 0.64 cm to 0.60 cm, respectively).
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DISCUSSION
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In this report, we describe quantitative changes to vessel shape depicted with MR angiography during treatment of brain metastases. Although the resolution of MR angiograms precludes examination of capillaries, a striking finding was the widespread distribution of tortuosity abnormalities at baseline. We determined the average vessel shape parameters over the entire brain. Although this analysis must have included uninvolved vessels, average vessel tortuosity values were abnormal for every patient at baseline. When we evaluated the vasculature, we found that tortuosity abnormalities could extend to even major named vessels lying outside apparent tumor confines. It is unknown whether these widespread abnormalities were related to the presence of disease that was indiscernible with gadolinium-enhanced imaging or to a general disorder of the intracerebral vasculature.
There was no apparent association between the initial MP and the subsequent reduction in MP. At baseline, patients tended to possess a lower vessel number and a smaller average radius than did healthy control subjects. Although this finding may appear paradoxical since cancer induces angiogenesis, two explanations are vessel drop out as a result of previous treatment or a reduction in the number of imaged vessels because of increased intracranial pressure or local pressure effects. Patients who exhibited improvement in MP at 2-month follow-up tended to exhibit an increase in vessel number at the second time point (4-month follow-up). One possible explanation for this phenomenon is reduction of mass effect. The variables that control the number of vessels seen on an MR angiogram are complex, and in previous studies researchers have concluded that tortuosity is more important than vessel number when assessing the tumor-associated vasculature seen on an MR angiogram (7,17).
One advantage of MR angiography as compared with traditional perfusion and permeability imaging is that individual vessels can be followed up over time. Our results show that vessel normalization includes not only reduction of vessel tortuosity but also alteration of vessel radii, with reduction of radii in some vessels and possible increase of radii in others. Previous reports have described both increases and decreases in blood volume after tumor therapy (18,19). Our methods cannot be used to assess permeability, but both permeability and tortuosity abnormalities might result from cancer-induced alterations to the vessel wall. One report suggests that perfusion and macroscopic vessel analyses yield independent information (20). New research is needed to correlate vascular information at the macroscopic (ie, MR angiogram) and microscopic (ie, blood volume and permeability) levels during longitudinal studies of tumor treatment.
An uncertanity is the effect of different therapeutic agents on tumor vasculature. Most studies in which vessel normalization is addressed involve the use of agents that oppose vascular endothelial growth factor. However, it seems reasonable to assume that any successful agent will exert some effect on tumor vasculature. The drug examined in this study, lapatinib, is a dual inhibitor of the epidermal growth factor receptor and ErbB-2 (HER2/neu) tyrosine kinase. The primary known effects are those on cell proliferation; however, since both epidermal growth factor receptor and HER2 may regulate vascular endothelial growth factor expression and since tyrosine kinase may promote angiogenesis, it is possible that lapatinib could have exerted some vascular effect.
Yet another unknown is the time course of vessel normalization as perceived with MR angiography. In our study, vessel normalization occurred in three patients after 2 months of chemotherapy; however, since we did not perform an interim examination, it is possible that vessel normalization occurred much earlier. If so, vessel morphologic analysis might allow separation of responders from nonresponders earlier during treatment.
A limitation of our study was that too few patients responded to therapy to permit us to draw definite conclusions about the value of using vessel tortuosity measurements to assess treatment response. Another limitation was that too few imaging time points were available to determine the time course of vessel normalization. A third limitation was that the control subjects were not age and sex matched to the patients. Nevertheless, our results demonstrate the feasibility of using noninvasive MR angiography to observe changes in vessel shape during tumor treatment. The initial results for prediction of therapeutic response appear promising.
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ADVANCES IN KNOWLEDGE
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- Noninvasive MR angiography can depict vascular morphologic changes during treatment of brain metastases in humans.
- A computer-assisted approach permits both quantitative measurement of vessel shape and visualization of vessel shape changes during treatment.
- Normalization or lack of normalization of abnormal tumor-induced vessel tortuosity may enable prediction of tumor treatment response.
- Individual vessels can be followed up over time to enable visualization and quantification of complex vascular alterations.
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IMPLICATION FOR PATIENT CARE
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- Changes in vessel morphology, as detected with noninvasive MR angiography, may be an early indicator of brain tumor response to chemotherapy, and these changes have the potential to allow early responsive adjustment of treatment tailored to an individual patient.
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FOOTNOTES
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Abbreviations: ICM = inflection count metric • MP = malignancy probability • RECIST = Response Evaluation Criteria in Solid Tumors • SOAM = sum of angles metric
Guarantor of integrity of entire study, E.B.; 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, E.B., N.U.L., E.P.W.; clinical studies, N.U.L., J.K.S., L.A.C., M.G.E.; statistical analysis, D.Z.; and manuscript editing, E.B., N.U.L., J.K.S., E.P.W., L.A.C., M.G.E.
Authors stated no financial relationship to disclose.
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ABSTRACT
INTRODUCTION
