|Year : 2019 | Volume
| Issue : 4 | Page : 818-824
Computed tomography-magnetic resonance imaging fusion-guided iodine-125 seed implantation for single malignant brain tumor: Feasibility and safety
Shi-Feng Liu1, Jian Lu2, Hong Wang3, Yan Han4, De-Feng Wang5, Li-Li Yang1, Zi-Xiang Li1, Xiao-Kun Hu1
1 Center for Interventional Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
2 Department of Radiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China
3 Department of Dermatology, Qingdao No. 6 People's Hospital, Qingdao, Shandong, China
4 Department of Science and Education, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
5 Department of Imaging and Interventional Radiology, The Chinese University of Hong Kong, Hong Kong, China
|Date of Web Publication||14-Aug-2019|
Center for Interventional Medicine, The Affiliated Hospital of Qingdao University, 1677 Wutaishan Road, Qingdao 266000, Shandong
Source of Support: None, Conflict of Interest: None
Background: To investigate the feasibility and safety of computed tomography-magnetic resonance imaging (CT-MRI) fusion-guided iodine-125 seed implantation for a single malignant brain tumor.
Methods: From November 2015 to October 2016, 12 patients with a single malignant brain tumor were treated with permanent iodine-125 seeds implantation. CT-MRI fusion images were used to make the preoperative treatment plan, intraoperative dose optimization, postoperative verification, and tumor response follow-up. The dosimetry parameters of CT-MRI image fusion plans were compared between preprocedures and postprocedures, including plan target volume, V100 (the percentage of the target volume covered by the prescription dose [PD]), D90 (the dose that covers 90% of the target volume), and V200 (the percentage volume of the brain tumor receiving 200% of the PD). Adverse events were graded by the Common Terminology Criteria for Adverse Events. Clinical and radiological follow-ups were performed at a 3-month interval.
Results: All the interstitial implantations were completed successfully under the guidance of CT-MRI image fusion. The dosimetry parameters of CT-MRI image fusion postplans did not differ significantly from those of preplans (P > 0.05). No higher than Grade 2 adverse events were observed during the follow-up. Tumor control was achieved in 10 of 12 patients (83.33%). The median overall survival time was 15.05 ± 3.35 months (95% confidence interval 12.99–17.26).
Conclusions: CT-MRI image fusion is feasible for the design, optimization, and verification of treatment planning. CT-MRI fusion-based brachytherapy may improve dosimetry of brain tumor while sparing the normal structures, potentially impacting disease control, treatment-related toxicity, and long-term survival.
Keywords: Brachytherapy, image fusion, malignant brain tumor
|How to cite this article:|
Liu SF, Lu J, Wang H, Han Y, Wang DF, Yang LL, Li ZX, Hu XK. Computed tomography-magnetic resonance imaging fusion-guided iodine-125 seed implantation for single malignant brain tumor: Feasibility and safety. J Can Res Ther 2019;15:818-24
|How to cite this URL:|
Liu SF, Lu J, Wang H, Han Y, Wang DF, Yang LL, Li ZX, Hu XK. Computed tomography-magnetic resonance imaging fusion-guided iodine-125 seed implantation for single malignant brain tumor: Feasibility and safety. J Can Res Ther [serial online] 2019 [cited 2019 Nov 20];15:818-24. Available from: http://www.cancerjournal.net/text.asp?2019/15/4/818/264299
| > Introduction|| |
Malignant brain tumors, referring to a heterogeneous group of primary intracranial malignancies (World Health Organization [WHO] Grades III/IV glioma) or brain metastases from systemic cancers (lung, skin, kidney, breast, and gastrointestinal tract), are life-threatening situations with a low survival rate.,, Currently, for newly diagnosed glioma, a multimodality treatment protocol consisting of surgical resection, radiotherapy, and chemotherapy is the first-line option. While at recurrence or metastasis, no standard approach (e.g., second surgery, re-irradiation, chemotherapy, or immunotherapy) has been established, and the survival of patients remains modest over the past decades despite efforts to advance protocols of therapy. Owing to the capability for local relapse, brachytherapy represents an option for selected patients with recurrent brain tumors and has demonstrated variable successes on outcome, although this has not been supported by prospective randomized evidence. Meanwhile, there exists some weakness of conventional brachytherapy, including the indefinite delineation of target tumor, dislocation of radioactive particles, and most importantly, the subsequently caused radiation-related adverse events.
Computed tomography (CT)-guided brachytherapy has been routinely used in spite of the complexity of the brain structures. Due to small differences in density, the interfaces between the normal brain tissue and tumoral tissue are ill-defined on CT scans. Magnetic resonance imaging (MRI), on the other hand, has a better soft-tissue resolution and shows the interfaces more distinctly. Recently, image fusion of MRI images with CT has been reported to be useful in radio-surgery, neurosurgery, and hypofractionated radiotherapy. Besides, in the brachytherapy of prostate cancer and cervical cancer, CT-MRI fusion has also become a valuable tool in the postimplant evaluation and improves the accuracy of postimplant dosimetry., This study aimed to investigate the feasibility and safety of a modified CT-MRI fusion technique in the preplan, intraoperative optimization, postoperative dose verification, and follow-up in permanent iodine-125 seed implantation (PISI) for single malignant brain tumor.
| > Methods|| |
Patients and materials
The study was approved by the local ethics committees. Written informed consent was obtained from each patient. Between November 2015 and October 2016, a total of 12 consecutive patients with single malignant brain tumor were treated by PISI under the guidance of CT-MRI fusion at our center.
The diagnosis of these patients were all confirmed by biopsy, including recurrent malignant gliomas (WHO III, 1 case and WHO IV, 5 cases) and metastases from extracranial cancer (3 from lung adenocarcinoma, 1 from small cell lung cancer, 1 from colon adenocarcinoma, and 1 from hepatocellular carcinoma, respectively). Of the six patients with recurrent malignant gliomas, two relapsed after surgery and four relapsed after external beam radiotherapy. Of the other six cases with distant metastases, neither surgery nor radiotherapy was performed on the metastatic intracranial lesions. In 33.3% of patients, the tumor was located in the temporal lobe. 25.0% of patients had a tumor in the parietal lobe. Systemic disease that was either not detectable or controlled with active treatment. Tumors in frontal and occipital lobes counted for 16.7% and 8.3% of patients, respectively. The remaining 16.7% of patients had a tumor in other areas. The baseline characteristics are presented in [Table 1].
Before the procedure, the patients were scheduled to undergo contrast-enhanced CT and MRI scans. Contrast-enhanced CT scans were performed on a GE Lightspeed CT-simulator at 120 kV, 150–280 mA, and field of view (FOV) 240 mm, with a slice thickness and slice gap of 5 mm. The orbitomeatal line (OML) was set as the baseline and scan range was from the base of the skull to cranial vault. CT images were obtained 45 s after injection of iohexol (Omnipaque, GE Healthcare, Boston, MA, USA) with the dose of 1.5 ml/kg and speed of 3 ml/s. Contrast-enhanced MRI scans were performed on a 3.0T MRI scanner (GE Signa HDx, Milwaukee, WI, USA) using the quadrature head coil at FOV of 240 mm, with a slice thickness of 5 mm and slice gap of 1.5 mm. The OML was set to be the baseline and the scan range was from the base of the skull to cranial vault. Contrast-enhanced MRI images were obtained 2 min after injection of Omniscan (Gadodiamide Injection, GE Healthcare, China) with the dose of 15 mL and speed of 2 ml/s. The interval between preoperative CT and MRI examinations was <3 days. Intra- and post-operative brain CT scanning was performed with the same scanning parameters of preoperative CT.
Before the treatment, the contrast-enhanced CT and MRI images were transferred to an imaging work station by the local area network. The fusion process was performed using a precommercialized brand-new software and data were saved as digital image communication format. Preoperative CT-MRI fusion images were further respectively fused with intra- and post-operative CT images by the fusion software to make the intraoperative optimization and postoperative verification.
Fusion is defined as an operation where two volumes are registered and resampled into one volume following a predefined formula. Typical fusions algorithms apply simple-weighted image addition, which can be described by the following equation (1):
I (x) = C1 I1 (x) + C2 I2 (x) (1)
Where (x ⊂ Ω)
Where I (x) is the value at voxel x of the fused image inside domain Ω. I1 (x) and I2 (x) represent voxels of two original images. C1 and C2 are weighted constant summing to 1. In addition to weighted factors, the fusion algorithm, we adopt also enables manual adjustment of the window and level of the fused images to visually emphasize lesions. The two-step algorithm follows the equations (2) (3) below:
I' k (x) = (Ik (x)–[lk-wk/2]) (Imax/w) (2)
I (x) = ρ (I'1 [x]) + ρ (I'2 [x]) (3)
Where ρ (y) = Imaxfor y > Imax
0 for y < 0
Where lk and wk are level and window settings of the image. Imax is the maximum grayscale pixel value of the image.
To facilitate segmentation, the fused image is downsampled into a desired number of slices along axial, coronal, or sagittal axes. The fusion software consists of three modules: medical image input module, data registration module, and medical image fusion and output module. Medical registration relies on the intensity-based similarity measure. Medical image fusion is based on both sparse representation and Laplacian pyramid.
Plan design and implementation
The preoperative CT-MRI fusion images were imported into the treatment planning system (TPS) (Beijing Astro Technology Ltd Co., Beijing, China) to generate the preplans [Figure 1]. In the preplan, the plan target volume (PTV), the entrance point and pathway of the needle, and parameters of dose distribution, including V100 (the percentage of the target volume covered by the prescription dose [PD]), D90 (the dose that covers 90% of the target volume), and V200 (the percentage volume of the brain tumor receiving 200% of the PD), were determined. According to various indicators such as the patient's external radiotherapy history, radiotherapy dose, peritumoral edema, and adjacent tumor threatening organs at risk, the corresponding personalized PD and seed activity could be ensured. The range of Iodine-125 seed activity (CIAE-6711; Chinese Atomic Energy Science Institution, Beijing, China) was 22.2 MBq to 29.6 MBq, and the range of PD was 100 Gy to 130 Gy. Accurate delivery of the determined dose to the target area and minimal damage to normal tissues were the primary goals of focus in the preplan design.
|Figure 1: Preoperative treatment planning based on computed tomography-magnetic resonance imaging fusion, (a and b) The green lines represented the needle pathway. The red cylinders on the needle pathway represented the distribution of seeds. The innermost purple circle showed V200. The inner blue circle represented plan target volume. The red circle represented V100 (the percentage of the target volume covered by the prescription dose). The outermost circle represented V50 (the percentage volume of the brain tumor receiving 50% of the prescription dose). The yellow circle showed organs at risk, (c) The dose-volume histogram of preplan calculated by the TPS (treatment planning system). It showed that D90 was 153.2 Gy, V100 was 96.8%, and V200 was 52.5%|
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Operation and intraoperative optimization
During the implantation, patients were asked to stay in a supine or lateral position for the convenience of operation. Seed implantation is usually performed under both general anesthesia and dural anesthesia. After intraoperative CT scanning, the computer based treatment planning process automatically starts, including image fusion with preoperative CT-MRI fused images, finding the optimal seed localizations and trajectories, and intraoperatively evaluating the validity of needle pathway and the distribution of seeds [Figure 2]. Vital signs were monitored during the operation.
|Figure 2: Intraoperatively, real-time evaluation based on computed tomography-magnetic resonance imaging fusion, (a) Intraoperative real-time evaluation of the validity of needle pathway and the distribution of seeds. The preoptimization intraoperative plan showed the V100 did not cover the plan target volume, (b) The preoptimization dose-volume histogram showed D90 was 113.8 Gy and V100 was 82.6%, (c) After real-time optimization, the red cylinders on the needle pathway represented the subsequently inserted seed. The postoptimization intraoperative plan showed that the V100 coincided with the plan target volume, (d) The postoptimization dose-volume histogram showed that D90 was 149.2 Gy and V100 was 97.0%|
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Postoperative treatment and dose verification
After implantation, steroids were administered routinely for several days with a daily decreasing dose of dexamethasone or methylprednisolone. The postoperative CT images were fused with preoperative enhanced CT-MRI images to make a postoperative verification by the TPS [Figure 3]. Treatment planning and parameter comparison were conducted by a physicist with 8 years of experience.
|Figure 3: Postoperative treatment planning based on computed tomography-magnetic resonance imaging fusion, (a and b) The yellow dots represented the distribution of inserted seeds, (c) The postoperative dose-volume histogram shows that D90 was 150.6 Gy and V100 was 97.2%|
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Follow-up and assessments
Toxicities were graded using the Common Terminology Criteria for Adverse Events; v4.03. Follow-up was carried out including clinical and radiological follow-up examinations (both CT and MRI) at an interval of 3 months. The modified Response Evaluation Criteria in Solid Tumors (mRECIST) was used in this study. Disease control rate (DCR) referred to the percentage of patients who had complete response, partial response, or stable disease.
Continuous numerical variables with normal distribution were presented as mean values with standard deviations (SD), while variables with nonnormal distribution were expressed as median. The PTV, D90, V100, and V200 between preplan and postplan were compared by the paired t-test. The survival curve was estimated using the Kaplan–Meier method. Statistical analysis was carried out using SPSS 19.0 (SPSS Inc., Chicago, IL, USA). A two-sided P < 0.05 was considered statistically significant.
| > Results|| |
The average number of seeds implanted per patient was 49.58 (range: 25–80). PISI under the guidance of CT-MRI fusion was successfully performed in all patients. The needles, implanted seeds, and their spatial relationship with the tumors can be demonstrated clearly on the intraoperative CT-MRI fusion image. Mean PTV, D90, V100, and V200 were 59.6 cm 3 (SD: 36.4), 126.0 Gy (SD: 9.7), 95.5% (SD: 1.3%), and 49.3% (SD: 4.0%), respectively, for the CT-MRI fusion preplan and were 59.9 cm 3 (SD: 36.7), 124.7 Gy (SD: 12.1), 95.3% (SD: 1.9%), and 49.6% (SD: 4.5%), respectively, for CT-MRI fusion postplan. All parameters above for CT-MRI fusion preplans did not differ significantly from those of postplan [Table 2], P > 0.05].
|Table 2: Comparison of parameters calculated by TPS between postoperative and preoperative planning|
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The rate of 30-day mortality was 0. In general, the incidence of adverse events was 25% (3/12) and no higher than Grade 2 adverse events were observed. One patient experienced Grade 1 cerebral edema-related headache but recovered in a few days without medical treatment. Grade 2 cerebral edema-related symptom (headache, nausea, and vomiting) was observed in one patient after treatment, which was resolved 1 week later after dehydration therapy by mannitol and system application of Glucocorticoids. One patient suffered Grade 2 bleeding-related headache but made a recovery in a week with symptomatic therapy.
According to the mRECIST assessment, DCR was noted in 10 of 12 cases (2 CR, 6 PR, and 2 SD, 83.3%) [Figure 4]. Follow-up ended in October 2017. The median follow-up period was 16.5 months (range 8.5–21.2 months). At the last follow-up, 5 patients (41.7%) were alive, and 7 patients (58.3%) were dead. Four patients died of multiple brain metastases, and three died of multiple organs failure. The median overall survival time was 15.1 ± 3.4 months (95% confidence interval [CI] 13.0–17.3). The median progression-free survival time was 12.3 ± 4.4 months (95% CI 9.8–15.4).
|Figure 4: Imaging follow-up based on computed tomography-magnetic resonance imaging fusion after implantation, (a) Preoperative computed tomography-magnetic resonance imaging fusion image showed that the tumor was located in the right temporal lobe, (b) Two months after implantation, seed distribution (high-density dots) can be demonstrated on computed tomography-magnetic resonance imaging fusion image. Compared with preoperative computed tomography-magnetic resonance imaging fusion image, the tumor size was reduced, the peritumoral edema and mass effect were relieved, and the shift of the middle structure disappeared|
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| > Discussion|| |
Our study demonstrates that CT-MRI fusion-based brachytherapy with idione-125 seeds is technically feasible and safe in the treatment of single malignant brain tumor. CT-MRI image fusion seems useful for preoperative plan design, intraoperative dose correction, postimplantation dosimetric assessment, and tumor response follow-up.
Historically, MRI has been the mainstay of imaging modality for brain tumor due to its advantages of the definition of the tumor boundaries with great soft-tissue resolution. Nevertheless, CT has been routinely used to guide the seed implantation due to its understanding of the spatial and anatomical relationships between tumors and surrounding structures., It has been reported that positron-emission tomography (PET) imaging may be useful in target volume delineation., This role has not been fully validated, however, and PET examination is relatively expensive to be widely used, especially in the undeveloped regions. Previous studies have demonstrated that the fusion with CT and MRI images will enable the delineation of the target for brachytherapy.,,, Enlightened from the previous results, we generate CT-MRI fusion images to guide PISI for the recurrent malignant brain tumor. Meanwhile, it is unique in terms of software and technique used in this study compared with the previous reports. This is a modified CT-MRI fusion technique dedicated to brain tumor brachytherapy. The algorithm was specifically developed to make the CT-MRI fusion into a quality-control tool to monitor the implantation process of malignant brain tumor brachytherapy.
These results show that the size, boundary, surrounding tissue of the tumor, and important vessels and brain tissues can be clearly delineated on the CT-MRI fusion image. Postoperative verification was performed 1 week after implantation because cerebral edema could occur in some patients within 1 week after PISI. In the present study, V100 achieved more than 95% in both the preplan and post verification based on CT-MRI fusion, Which seems better than that of CT-based plan which is around 90%. Besides, the other dosimetry parameters, including PTV, D90, and V200, maintain a good consistency between the pre- and post-plans after intraoperative optimization based on CT-MRI fusion.
The fusion of postoperative CT-MRI images with the previous planning images, including the isodose distribution, helps analyze the quantitative variations of necrosis, the reactive zone, and edema (triple ring). This technique might provide more information to monitor tumor recurrence other than the measurement of volume changes alone. During the follow-up, the rate of DCR was recorded among 83.3% of patients, which suggested that a satisfactory local control was obtained using CT-MRI-guided brachytherapy.
In this study, pre- and intra-operative fusion imaging provided easy control of the implantation applicator and reduced the risk of damaging the surrounding brain tissues and vessels. No higher than Grade 2 complications were recorded during or after the procedure. One-fourth of patients had mild-to-moderate bleeding or edema-related symptoms but all of them relieved and recovered during the follow-up. Small amounts of bleeding occurred in the brain of one patient, which may be caused by the complex distribution of small vessels in the brain. No symptomatic hemorrhage occurred during the follow-up, which suggested that permanent brachytherapy under the guidance of CT-MRI fusion was well tolerated.
The role of brachytherapy has been limited to be a salvage choice for a very select group of patients with recurrent lesions or metastases due to the unsatisfactory survival benefit. Various median survival times ranging from 9 to 35 months have been reported for recurrent high-grade gliomas after brachytherapy. Brain metastases have been historically associated with a dismal prognosis and a median survival range of 2.79–25.30 months, which is related to how well the primary cancer is controlled. In the present cohort, a survival benefit with a median survival of 15.4 months was obtained, which appears longer than that obtained using a conventional CT-based brachytherapy, resurgery, or external beam radiotherapy.,, This implies that these patients may benefit from CT-MRI fusion-based brachytherapy.
This study had several limitations. First, the number of patients was small. Further studies involving more patients are needed to establish the proposed method.
Second, the noncontrolled nature of this study does not provide enough evidence of the efficacy of CT-MRI fusion-based brachytherapy on overall survival. Further prospective controlled studies with are warranted to yield more convincing results.
| > Conclusions|| |
In summary, CT-MRI image fusion is feasible for design, optimization, and verification of planning. CT-MRI fusion based brachytherapy may impact disease control, treatment-related toxicity, and the long-term survival.
We would like to thank Ji-Hua Liu for his assistance in image reading. We also thank Chu-Hui Zeng for polishing the manuscript.
Financial support and sponsorship
This study was funded by the Shandong medical science and technology development project (2014WSB26020).
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]