J Neurooncol (2010) 99:81–88 DOI 10.1007/s11060-009-0106-z
CLINICAL STUDY - PATIENT STUDY
Perfusion weighted magnetic resonance imaging to distinguish the recurrence of metastatic brain tumors from radiation necrosis after stereotactic radiosurgery Koichi Mitsuya • Yoko Nakasu • Satoshi Horiguchi • Hideyuki Harada • Tetsuo Nishimura • Etsuro Bando • Hiroto Okawa • Yoshihiro Furukawa Tatsuo Hirai • Masahiro Endo
•
Received: 18 October 2009 / Accepted: 23 December 2009 / Published online: 8 January 2010 Ó Springer Science+Business Media, LLC. 2010
Abstract After stereotactic radiosurgery (SRS) for brain metastases, delayed radiation effects with mass effect may occur from several months to years later, when tumors may also recur. Aggressive salvage treatment would be beneficial for patients with recurrence, but may be contraindicated for those with dominant radiation effect. Conventional magnetic resonance (MR) imaging does not provide sufficient information to differentiate delayed radiation effects from tumor recurrence. Positron emission tomography, MR spectroscopy, and other modalities sometimes may lead to false findings of tumor recurrence. We prospectively applied perfusion MR imaging for the management strategy after SRS because it gives microvascular information about the lesions. Twenty-eight lesions were enlarged on serial MR images in 27 patients 2–35 months (median: 11.8 months) This paper was presented at the Eighth Biannual Congress of the International Stereotactic Radiosurgery Society, in San Francisco, June 2007. K. Mitsuya (&) Y. Nakasu S. Horiguchi Division of Neurosurgery, Shizuoka Cancer Center, Sunto, Japan e-mail:
[email protected] H. Harada T. Nishimura Division of Radiation Oncology, Shizuoka Cancer Center, Sunto, Japan E. Bando Division of Gastric Surgery, Shizuoka Cancer Center, Sunto, Japan H. Okawa Y. Furukawa M. Endo Division of Diagnostic Radiology, Shizuoka Cancer Center, Sunto, Japan T. Hirai Gamma Unit Center, Fujieda Heisei Memorial Hospital, Fujieda, Japan
after SRS for metastatic brain tumors. Each patient underwent MR perfusion imaging within a month after appearance of the growing enhanced lesion. To calculate the relative cerebral blood volume ratio (rCBV ratio), the regions of interest were located in the enhanced areas on the contrastenhanced T1-weighted images and compared with the corresponding contralateral normal brain tissue. They were then followed-up with scheduled MR images with gadolinium enhancement at 1 to 2-month intervals afterward. Lesions which progressively increased in size on MR images were diagnosed as recurrences; lesions which disappeared or decreased in size were diagnosed as radiation necrosis. In addition, two lesions surgically removed were diagnosed by pathological examination. Follow-up MR images revealed that 21 of 28 lesions were radiation necrosis. Five lesions were diagnosed as recurrence on MR images, and the other two lesions were revealed as recurrence by pathological examination. An rCBV ratio of greater than 2.1 provided the best sensitivity and specificity for identifying recurrent metastatic tumors, at 100 and 95.2%, respectively. Perfusion MR imaging provides useful, less invasive and in-vivo information for management of growing lesions after SRS, and rCBV may be a valuable index for this diagnostic purpose. Keywords Cerebral metastases Radiation effect Perfusion MR imaging
Introduction Brain metastases occur in 20–40% of all patients with cancer [1]. Recent advances in systemic management for cancer patients have led to an increasing population of long-term survivors with brain metastases. Stereotactic radiosurgery
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(SRS) has become an important therapeutic adjunct for patients with metastatic brain tumors. Patient survival and quality of life largely depend on control of neoplasms, recurrence, and adverse effects of therapy. Radiation effects and necrosis causing edema and mass effect in the brain have become increasingly important after aggressive management for brain metastases. Autopsy studies of patients who underwent SRS for brain metastasis demonstrated a mixture of necrosis and surviving neoplastic cells as early as three weeks after treatment [2]. Tumor recurrence, radiation necrosis, and their mixture have a similar appearance as progressive contrast enhancement on conventional contrastenhanced magnetic resonance (MR) imaging. On the basis of images of progressively enhanced lesions we have to decide whether to proceed to a salvage treatment or to wait and see, with conservative medical care. MR spectroscopic examinations and positron emission tomography (PET) have been used, with mixed success, to differentiate adverse radiation necrosis from recurrence [3–6]. Perfusion computed tomography (CT) and MR imaging have been used for imaging cerebral circulation factors in vascular diseases and tumors [7, 8]. MR imaging seems superior to CT scan by providing better anatomical resolution and less risk of adverse effects by ionizing radiation and iodine contrast medium used for perfusion CT scan. Among various perfusion-related properties of the brain, cerebral blood volume (CBV) has been the most common and valuable discriminator of tumor grades in MR images reflecting tumor microvascular density [9–14]. We hypothesize that CBV measured by perfusion MR enables one to predict growth as recurrence of a progressively enhancing lesion after SRS, and that the information may contribute to non-invasive selection of patients who need salvage treatment.
Methods Patient selection and final diagnosis Our institutional review board approved this prospective study, and informed consent was obtained from the participants before examinations. The study represented part of their clinical evaluation. Between August 2003 and May 2008, a total of 27 patients were evaluated with perfusion MR when they had a progressive enhancing lesion on follow-up MR images after SRS for brain metastases. Patients presenting a progressive enhancing lesion after stereotactic radiosurgery (SRS) or radiotherapy (SRT) for metastatic brain tumor were eligible. They should have diagnosis of primary systemic cancer, and two consecutive MR images showing enhancing enlarging lesions within the radiation field. Concomitant whole-brain radiation was allowed. Patients with concurrent renal dysfunction or
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contraindications for magnetic resonance contrast imaging were excluded. One patient with lung cancer presented two separate lesions to be studied on different occasions. The ages ranged from 38 to 85 years with a mean age of 59.6 years. Exclusion criteria were serious cardiopathy, pregnancy, or contraindications to contrast agent administration. Patient condition and lesions were thereafter regularly evaluated by clinical manifestations and routine MR imaging every 1–3 months. We made final diagnosis of a radiation necrosis when a focused lesion showed complete response, partial response, or stable disease depending on the response evaluation criteria in solid tumor (RECIST) method on subsequent follow-up MR images for a minimum of three months. If the lesion presented with progression on serial MR examination and the patient deteriorated progressively in neurological condition, we diagnosed the case as tumor recurrence. Those patients underwent salvage radiation therapy or surgical removal of the lesions. Perfusion MR technique Perfusion images were obtained with the aid of a 1.5-T unit (Gyroscan Intera 1.5 Master, Philips, The Netherlands) by echo-planar image (EPI) sequence using the dynamic susceptibility contrast-enhanced technique with the following settings: TR 500 ms, TE 33 ms, field of view 220 mm, matrix 128 9 128, thickness 6 mm, slice gap 1.2 mm, number of slices 3. Dynamic contrast-agent-enhanced EPI were acquired during the first pass following a rapid injection of a 0.1 mmol/kg bolus of gadopentetate dimeglumine via a mechanical pump at a rate of 5 ml/s, followed by a 30-ml bolus of saline through a 20-gauge intravenous line to a cubital vein. For preloading, 0.05 mmol/kg contrast medium was injected before bolus injection, to minimize the effect of T1 shortening from enhancing lesions [15, 16]. In the MR unit, 2D images were constructed, and were transferred to a workstation; relative cerebral blood volume (rCBV) maps were generated and analyzed on a voxel-byvoxel basis from the dynamic imaging data using Philips Easy Vision. Conventional and perfusion MR images were taken during the same session. Unenhanced images were used to select any three axial sections for perfusion imaging, and to locate regions of interest (ROIs) on the workstation. Image evaluation To calculate rCBV ratios (rCBV tumor/rCBV contralateral brain tissue), ROIs consisting of more than 20 pixels were located in an enhanced lesion on contrast-enhanced T1-weighted images and in the contralateral white matter which was found normal on both T2-weighted and contrastenhanced T1-weighted images. The ROIs were located
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completely within the lesion by hand, avoiding major cortical vessels and cystic parts of the lesion by an observer unaware of the clinical data. If a patient had multiple progressing enhancing lesions, the largest was selected for this analysis. Pathological analysis Two lesions of two patients were histologically verified. Surgical specimens were fixed in neutral formalin, and were embedded in paraffin. Histological sections were stained with hematoxylin and eosin, and were examined with a light microscope by pathologists.
Statistical analysis Descriptive statistics (medians and others) for each property were computed. Statistical analysis was performed using commercially available software (JMP, version 7.0). The values of rCBV ratio for tumor recurrence and radiation effect were compared by use of the Mann–Whitney nonparametric test. Significance was defined as a probability value of less than 0.05. Sensitivity was defined as the proportion of correctly identified recurrent tumors, and specificity was defined as the proportion of correctly identified radiation necroses. Receiver-operating characteristic (ROC)
Table 1 Clinical characteristics and rCBV ratios No.
Sex/age
Origin
Diameter
Previous radiation
RT dose TTP rCBV F-U Imaging (Gy) (M) ratio period outcome
1
M/61
Esophagus
29
SRT
35
4
2
M/58
Colon
25
WBRT, GKS
50, 25
6
3
F/61
Lung (adeno) 18
SRS
20
17
6
4
F/62
Breast
12
WBRT, SRS
40, 15
16
3.5
5
F/39
Breast
28
WBRT, SRT
40, 24.5
6
6
F/38
Breast
11
SRS
25
7
M/54
Lung (adeno) 21
CK, WBRT
20, 30
Treatment
Recurrence
Median
21
10
3
PD
Glycerol, steroid
4
PD
Glycerol, steroid
21
PD
Radiation (SRT), chemotherapy
5
PD
Glycerol, steroid
2.4
11
PD
Radiation (GKS)
25
2.1
3
PD
Surgery
9
2.1
9
PD
Surgery
9
3.5
5
6.08
No recurrence (radiation necrosis) 8
F/69
Breast
25
SRT
35
12
2.57
5
SD
Steroid
9
F/60
Breast
21
SRS
25
18
1.6
3
PR
Steroid
10
F/56
Breast
5
GKS
20
35
1.6
31
PR
None
11
M/62
Lung (adeno) 17
SRS
25
19
1.33
9
SD
Steroid
12 13
F/82 M/69
Breast 7 Lung (adeno) 15
GKS WBRT, SRS
20 30, 15
13 2
1.23 1.14
7 8
PR PR
Steroid None
14
F/60
Lung (adeno) 18
SRS
21.4
15
1.06
8
SD
Steroid
15
M/71
Esophagus
23
SRS
20
17
1.04
3
SD
Glycerol, steroid
16
M/64
Lung (adeno) 20
SRS
25
4
1
20
PR
Steroid Steroid
17
M/57
Lung (adeno) 12
GKS 9 2
30 9 2
5
1
3
SD
18
M/85
Lung (small)
9
SRT
24
4
1
3
PR
None
19
F/41
Breast
16
SRS
25
3
0.83
3
PR
Steroid
20
M/52
Lung (adeno) 21
WBRT, SRT
40, 20
18
0.75
13
PR
Steroid
21
M/62
Lung (adeno) 11
SRS
25
8
0.74
5
PR
None
22
M/48
Lung (adeno)
8
SRS
25
7
0.73
32
SD
Steroid
23
F/52
Breast
10
SRS
25
20
0.68
6
SD
Glycerol, steroid
24
M/59
Lung (adeno) 30
GKS
20
6
0.55
3
SD
Steroid
25
F/43
Lung (adeno) 20
WBRT, GKS
30, 17
3
0.49
13
SD
Glycerol, steroid
26
M/58
Colon
27
SRS
25
6
0.4
3
PR
Steroid
27 28
M/82 F/63
Lung (adeno) 17 Lung (adeno) 25
SRS GKS
25 20
24 8
0.4 0.34
28 13
SD PR
None Steroid
Median
17
8
1
7
TTP, time to progression; WBRT, whole-brain radiation therapy; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; CK, cyberknife radiosurgery; GKS, gamma knife radiosurgery One patient (#3 and #7) had two lesions on separate occasions
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curve analysis was used to determine the optimum index of perfusion MR and cut-off values for the differential diagnosis of tumor recurrence and radiation effect. Results Twenty-seven patients underwent a total of 28 perfusion MR examinations for differentiation of growing enhanced mass after previous SRS (Table 1). Twenty of the 27 patients had undergone radiosurgery by liniac; the median diameter of the mass lesions was 25 (range: 15–30) mm, and the median marginal dose was 18 (range: 10–25) Gy at 90% dose. One of the 20 patients underwent radiosurgery for two lesions on separate occasions. The other seven patients had undergone gamma knife radiosurgery; the median diameter of the mass was 25 (range: 14–28) mm, and the median marginal dose was 20 (range: 10–30) Gy. The median interval between SRS treatment and enlargement of the lesion was 11.8 (range: 2– 35) months. Until final determination of recurrence or radiation effect, the patients underwent follow-up MR imaging two to six times during 2–15 months. Two patients underwent surgical removal because of progressive mass effects of their lesions, which were confirmed as active recurrent tumors by pathological evaluation. As a consequence, seven (25%) lesions were found to be recurrent metastases, and 21 (75%) were radiation effect in this study
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median rCBV ratio between the two entities was significant (P \ 0.0001). ROC curve analysis was used to assess the diagnostic utility of the metrics to discriminate recurrence from radiation effects. The ROC curve for the rCBV ratio is shown in Fig. 2. The optimum rCBV value for differentiating tumor recurrence from radiation effect was 2.1, giving an accuracy profile of the best sensitivity and specificity for metastatic brain tumors, 100 and 95.2% respectively. The area under the ROC curve of 0.98 indicates high sensitivity and specificity. In this study, rCBV ratio ranged from 0.34 to 10: higher than 2.1 for all seven cases of recurrent metastases, and lower than 2.1 for all cases of radiation effect except one. Illustrative cases
The rCBV ratio of the lesions ranged from 0.39 to 2.57 (median 1.0) for radiation effect and from 2.1 to 10 (median 3.5) for recurrent metastases (Fig. 1). The difference in
Case 1: A 38-year-old woman presented with a single asymptomatic parietal lesion on screening head MR images after surgery for breast cancer (Fig. 3a). The lesion was treated with SRS at a dose of 25 Gy for 95% margin. Five months after SRS, MR images showed it had decreased in size and in heterogeneous signal intensity (Fig. 3b). However, follow-up MR images showed the lesion increased in size and surrounded with perifocal edema 25 months after SRS, when perfusion MR images showed obvious increase in CBV and an increased rCBV ratio of 2.1 relative to the corresponding site (Fig. 3c, d). Our diagnosis was recurrent metastasis even though she had shown no neurological deterioration. The patient underwent surgical removal. Pathological examination confirmed an adenocarcinoma with a small volume of radiation effect in the region of high CBV (Fig. 3e).
Fig. 1 Box-and-whisker plots of each rCBV ratio for tumor recurrence and radiation necrosis. Horizontal bars inside boxes indicate medians. Error bars indicate farthest points that are not outlines. There was a significant difference between rCBV ratio of tumor recurrence and radiation necrosis (P \ 0.0001)
Fig. 2 ROC curve for rCBV ratio of metastatic brain tumors which recurred after radiosurgery. Az was 2.1 for rCBV ratio
Statistical results
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Fig. 3 Contrast-enhanced T1-weighted axial MR images obtained in a patient with metastatic tumor from breast cancer, immediately after SRS (a), 5 months after SRS (b), 9 months after SRS (c). Perfusion
MR image demonstrating increase in rCBV within an ROI in the right parietal region compared with the contralateral side (d). Photomicrograph depicting typical adenocarcinoma in necrotic tissue (e)
Case 2: This 52-year-old woman presented with left homonymous visual field defect during chemotherapy for metastatic liver tumor after surgery for breast cancer. A single brain metastasis in the right occipital lobe was treated with SRS at a dose of 25 Gy for 95% margin (Fig. 4a). Six months after SRS, the lesion had shrunk on MR images, and her visual field had improved (Fig. 4b). However, the lesion increased in size, with recurrent left homonymous visual field defect at 20 months after SRS (Fig. 4c). Perfusion MR images showed decreased rCBV of the lesion, with an rCBV ratio 0.68 (Fig. 4d). The case was diagnosed as radiation effect, and a mild dose of steroid was prescribed. Thereafter, the patient’s condition showed no changes for some months, and follow-up MR images showed slight shrinkage of the lesion at 25 months after SRS (Fig. 4e).
of microvasculature in lesions after SRS, which provides important information for differential diagnosis for better clinical decisions. In recent years, brain metastases have become candidates for aggressive treatment leading to increased survival, and also to new problems and issues in neuro-oncology associated with subacute and chronic adverse effects of treatments, which we had not encountered in the era of more often devastating outcomes in patients with brain metastases. Modern high-dose conformal radiation therapy such as SRS has been used frequently to treat patients with brain metastasis [20]. One of the issues is differentiating tumor recurrence from radiation effect because the management strategies for these two entities are totally different. The time interval from SRS to development is about the same for both sorts of lesion, and provides no ideas for differentiation. Standard diagnostic techniques cannot reliably discriminate between the adverse effects of SRS and true tumor recurrence.
Discussion This study demonstrated that recurrent metastasis or radiation effect after SRS can be differentiated by rCBV ratio on perfusion MR images, given a threshold value. Our threshold value cannot be applied universally, for it was derived from results from one MR machine and software in a specific institute; MR perfusion imaging provides only semiquantitative data because of a non-linear relationship between signal and contrast concentration [17–19]. Nevertheless, our results suggest rCBV enables in-vivo assessment
Conventional MR imaging As for recurrent tumor and radiation effect, conventional MR images demonstrate an enhancing lesion, sometimes a ring enhancement, with edema and mass effect, but these are nonspecific findings (Sugahara). Serial MR images show progressive, stable, or subsiding changes of lesions and perifocal edema.
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Magnetic resonance spectroscopy (MRS) Single-voxel MRS reportedly showed a sensitivity of 75%, and multivoxel MRS a sensitivity and specificity of 100% [3]. Using 3-T MRS, sufficient spatial resolution and chemical specificity were reported to enable distinction of recurrent tumors versus radiation effect [21]. MRS offers an advantage in providing tissue chemical data and in performance without contrast media, although it still has problems of limited availability of machines and techniques. Positron emission tomography (PET) According to the literature, 18F-FDG PET provided a sensitivity of 75% and specificity of 81–94% in diagnosis of recurrent brain tumors [22, 23]. Chao et al. reported better sensitivity and specificity with corecording of 18F-FDG PET and MR images [22]. Accumulation of 18F-FDG occurs preferentially in normal gray matter, but this provides poor contrast between neoplastic lesions and normal brain. PET with 11C-methionine (Met) was also reported
Fig. 4 Contrast-enhanced T1-weighted axial MR images obtained in a patient with metastatic tumor from breast cancer, immediately before SRS (a), 6 months after SRS (b), 20 months after SRS (c). Perfusion MR image demonstrating decrease of rCBV within an ROI
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useful to differentiate between tumor and necrosis [6, 24]. However, the level of 11C-Met uptake in necrotic tissue is elevated, as 11C-Met is thought to accumulate in tissue with a disrupted blood–brain barrier [6, 25]. PET scan is more difficult to interpret [26]. Limited availability of hardware, irradiation, and cost are also of limitations of PET study. Single-photon emission computed tomography (SPECT) Thallium SPECT reportedly showed tumor tissue as a hot area, but its sensitivity was 69–91% and specificity 40–90.5% [26, 27]. Its availability is also limited, and radioactive medium is necessary for examination. Computed tomography (CT) perfusion study Perfusion CT scans provides more quantitative information about perfusion than does perfusion MR, because CT scan has a more linear relationship of attenuation and contrast agent concentration than MR imaging. However, it is still
in the right temporo-occipital region compared with the left side (d). Contrast-enhanced T1-weighted axial MR image showing reduced size of the lesion (e)
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limited in reproducibility of absolute values, and as yet only relative values have been used for clinical study. Jain et al. reported that their recurrent tumor group showed statistically significant increase in mean normalized (relative) CBV and decrease in normalized mean transit time compared with their radiation necrosis group [7]. The disadvantages of CT perfusion study include exposure to ionizing radiation, higher risk from adverse reactions to relatively large volumes of iodine contrast medium, and lower anatomical resolution [13]. With the recent availability of 320row multidetector CT scanners, perfusion CT can provide a wider coverage, lower exposure and more sophisticated data acquisition of vascular images than with usual CT machines.
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SRS, and rCBV may be a valuable index for this diagnostic purpose. The time course for rCBV changes and comparison between perfusion and metabolic studies would be interesting and may contribute to patients, predicting effects and outcome of radiation therapy. Additional studies are necessary to validate our results in long-term management including salvage treatments for patients with brain metastasis. Acknowledgments We are grateful to Mr. Piers Vigers for his assistance in editing the manuscript, to Dr. Satoshi Nakasu, M.D., Division of Neuro-oncology, Kusatsu General Hospital, for his special advice, and Dr. Reiko Watanabe, M.D., Division of Pathology, Shizuoka Cancer Center, for her support in pathological description.
MR perfusion study References Perfusion-weighted MR provides noninvasive physiological measurements of tumor vascularity and relative CBV maps, which can be used to identify areas of neovascularization, in contrast with conventional MR techniques [28, 29]. Many methods using endogenous or exogenous tracers have been developed to image various properties related to brain perfusion [14]. Although the relationship between these properties and the MR signal is complex, injection of paramagnetic contrast agents for measurement of CBV has been successful [30]. Several reports have been published on the usefulness of perfusion MR imaging in grading of gliomas [9, 13, 31]. We examined metastatic brain tumors that were more segregated than gliomas that are invasive, heterogenous, and mixed with reactive cells. Accurate selection of ROI within the lesion enables good sensitivity and specificity in differentiating recurrent metastatic tumor from dominating radiation effects. We suggest that analysis of perfusion MR is helpful in managing brain metastasis, especially for patients with questionable increase in size of the target lesion and surrounding edema within a few years after SRS. One must be careful to distinguish mixed tissues of recurrence and radiation effects. For perfusion MR study, values and thresholds are not universal, but are unique for each MR machine, sequence, or institute. Further study in larger populations would be necessary for accurate diagnosis leading to more appropriate management for survivors.
Conclusion Aggressive treatment strategies for systemic cancer and brain metastasis have improved patients’ quality of life with longer expectancy, necessitating chronic management and salvage treatment after SRS for brain metastases. Perfusion MR imaging provides useful, less invasive and in-vivo information for the management of growing lesions after
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