Using Higher Isodose Lines for Gamma Knife Treatment of 1 to 3 Brain Metastases Is Safe and Effective
Shiue, Kevin BS*; Barnett, Gene H. MD, MBA‡,§; Suh, John H. MD‡,¶; Vogelbaum, Michael A. MD, PhD*,‡; Reddy, Chandana A. MS¶; Weil, Robert J. MD‡,§; Angelov, Lilyana MD‡,§; Neyman, Gennady PhD¶; Chao, Samuel T. MD‡,¶
*Case Western Reserve University School of Medicine, Cleveland, Ohio;
‡Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center;
§Department of Neurosurgery, Neurological Institute;
¶Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
Correspondence: Samuel T. Chao, MD, Cleveland Clinic Lerner College of Medicine, Department of Radiation Oncology, Desk T28, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: firstname.lastname@example.org
Received October 02, 2013
Accepted January 02, 2014
BACKGROUND: Higher isodose lines (IDLs) in Gamma Knife (GK) Perfexion treatment of brain metastases (BMet) could result in lower local control (LC) or higher radiation necrosis (RN) rates, but reduce treatment time.
OBJECTIVE: To assess the impact of the heterogeneity index (HI) and conformality index (CFI) ion local failure (LF) for patients treated with GK for 1 to 3 BMet.
METHODS: From an institutional review board—approved database, 320 patients with 496 BMet were identified, treated for 1 to 3 BMet from July 2007 to April 2011 on GK Perfexion. Cox proportional hazards regression was used to analyze significance of HI, CFI, IDL, dose, tumor diameter, recursive partitioning analysis class, tumor radioresistance, primary, smoking history, metastasis location, and whole-brain radiation therapy (WBRT) history with LF and RN.
RESULTS: Median follow-up by lesion was 6.8 months (range, 0-49.6). The series median survival was 14.2 months. Per RECIST, 9.5% of lesions failed, 33.9% were stable, 38.3% partially responded, 17.1% responded completely, and 1.2% could not be assessed. The 12-month LC rate was 87.3%. On univariate analysis, a dose less than 20 Gy (hazard ratio [HR]: 2.940, P < .001); tumor size (HR: 1.674, P < .001); and cerebellum/brainstem location vs other (HR: 1.891, P = .043) were significant for LF. Non-small cell lung cancer (HR: 0.333, P = .0097) was associated with better LC. On multivariate analysis, tumor size (HR: 1.696, P < .001) and cerebellum/brainstem location vs other (HR: 1.959, P = .033) remained significant for LF. Variables not significant for LF included CI, IDL, and HI.
CONCLUSION: Our study of patients with 1 to 3 BMet treated with GK demonstrated no difference in LC or RN with varying HI, indicating that physicians can treat to IDL at 70% or higher IDL to reduce treatment time without increased LF or RN.
ABBREVIATIONS: BMet, brain metastases
CFI, conformality index
CI, confidence interval
CR, complete response
GK, Gamma Knife
HI, heterogeneity index
HR, hazard ratio
IDL, isodose line
LC, local control
LF, local failure
MVA, multivariate analysis
NSCLC, non-small cell lung cancer
PR, partial response
RECIST, Response Evaluation Criteria in Solid Tumors
RN, radiation necrosis
RTOG, Radiation Therapy Oncology Group
SD, stable disease
SRS, stereotactic radiosurgery
UVA, univariate analysis
Brain metastases (BMet) are the most common neurological complication of cancer, with 200,000 cases per year and BMet developing in 8% to 10% of cancer patients. Most BMet originate from primary cancers of the lung (40%-50%), breast (15%-25%), or skin (melanoma, 5%-20%).1 As detection of and therapies for both primary cancers and BMet have improved, patients with systemic disease are now living long enough to develop more BMet. Treatment options for BMet include surgery, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), chemotherapy, or some combination of these modalities.
SRS with Gamma Knife (GK) precisely delivers high-dose radiation with minimal radiation to surrounding tissue. This modality can be used to treat up to 4 lesions in disparate locations2—and potentially 5 or more metastases as well3,4—with excellent local control. SRS with WBRT has demonstrated significantly improved 1-year rates of survival, intracerebral control, and local control (LC), with outcomes comparable to those of surgery with WBRT.5 SRS is also used as the sole modality in patients previously treated with WBRT or in patients with concerns of neurotoxicity. SRS is an important option in patients who are not surgical candidates because radiosurgery is a minimally invasive, single-day outpatient procedure.2
There are several proposed measures of dose conformity used during GK planning. At our institution, we use the conformality index (CI) and heterogeneity index (HI). Based on the Radiation Therapy Oncology Group (RTOG) 90-05 randomized trial, the isodose line (IDL) when generating treatment plans for SRS should be 50% or higher to minimize toxicity.6 In GK, the IDL is typically 50% to 60% to take advantage of the rapid dose falloff and higher central dose. This is in contrast to LINAC-based radiosurgery in which the IDL is typically 80% or higher. The HI is essentially the inverse of IDL, and HI values are generally kept at 2.0 or less during planning.
The Elekta GK Perfexion system (Elekta AB, Stockholm, Sweden) can achieve plans that are highly conformal to the target. However, there is concern that an improved CI may lead to an increased rate of recurrence at the margins when SRS is applied to the tumor bed after resection of the BMet.7 It is unknown whether this holds true for lesions treated only with radiosurgery. Since the adoption of the Perfexion system at our institution, some of our plans have become increasingly conformal. In addition, higher IDLs have been used to decrease treatment time to take advantage of the machine's simplicity in treating multiple metastases.
We report our institutional experience with GK for 1 to 3 BMet via a retrospective review of patients treated with the Perfexion system since July 2007, specifically looking at the impact of dosimetric factors, particularly the HI/IDL and CI, on LC and toxicity.
PATIENTS AND METHODS
In this retrospective review, patients with a maximum of 3 brain or brainstem metastases treated from July 2007 to April 2011 treated with GK Perfexion system were identified on an institutional review board—approved database. These patients had not been treated with GK at all previously.
The Elekta GK Perfexion system was used in all patients. The target was contoured and dose planning was performed with coregistered contrast-enhanced computed tomography and magnetic resonance imaging (MRI). Two indices were calculated for all patients: an HI, defined as maximal dose/prescribed dose, and a CI, defined as the prescribed isodose volume/target volume. Dosing schemes generally followed the results of the RTOG 90-05 randomized trial based on the maximum dimension of the lesions treated6 (Table 1). All patients were scored according to the recursive partitioning analysis prognostic system.
Most patients were followed with at least a 1-month post-treatment MRI scan and serial follow-up imaging every 3 to 6 months. Lack of follow-up was typically because the patient declined too quickly or because the patient chose to receive follow-up care elsewhere. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to assess the degree of response in patients who had at least the 1-month scan (patients without follow-up were coded as inconclusive). A complete response (CR) was defined as a complete disappearance of the lesion. A partial response (PR) was defined as ≥30% reduction in the size of the lesion. Local failure (LF) or progressive disease was defined as a 20% or greater increase in the size of the lesion. All others, if not designated inconclusive, were designated as stable disease (SD). Lesions that did not progress (ie, CR, PR, SD) were considered locally controlled.
The natural history and additional imaging were used to differentiate radiation necrosis (RN) and tumor recurrence. The diagnosis of RN was determined sometimes by biopsy, but most often by analyzing post-treatment cerebral blood volumes with MRI perfusion studies. Less commonly, 18-fluorodeoxyglucose positron emission tomography was used. In cases of uncertain diagnosis, the lesion was independently reviewed by one of the authors (S.T.C.) to make a diagnosis for the purposes of this article. Lesions diagnosed in this manner were not excluded from the study.
LC and overall survival outcomes were calculated using the Kaplan-Meier estimation.8 Prognostic factors for LC and RN were separately assessed using Cox proportional hazards regression analysis.9 Because many patients had multiple lesions, prognostic factors were analyzed on a per-lesion basis. Both univariate and multivariate analyses were performed for local LF and RN. Statistical significance was determined with a P value of ≤.05. Statistical analysis was performed using SAS version 9.2 (SAS Institute, Cary, North Carolina) and R version 2.13 (R Foundation for Statistical Computing, Vienna, Austria).
Patient, lesion, and treatment characteristics are shown in Table 2. A total of 320 patients (183 female and 137 male) with 1 to 3 BMet (total of 496 lesions) were included. The most frequent histologies were non-small cell lung cancer (NSCLC; n = 233, 47.0%), breast cancer (n = 95, 19.2%), renal cell carcinoma (n = 56, 11.3%), melanoma (n = 43, 8.7%), small-cell lung cancer (n = 33, 6.7%), and a variety of other histologies (n = 36, 7.3%). WBRT was used to treat 259 lesions (139 were treated before GK, 60 were treated concurrently, and 60 were treated as salvage). The median age at treatment was 60 years of age (range, 29-92 years), the median Karnofsky Performance Status score was 80 (range, 50-100), and the median follow-up time by MRI was 6.8 months (range, 0-49.6 months). The median prescription dose was 24 Gy (range, 10-24 Gy) and the median CFI and HI were 1.62 (range, 1.11-5.7) and 1.896 (range, 1.067-2.042), respectively.
The median survival time for the series after the date of GK was 10.2 months. The 6-, 12-, and 18-month actuarial rates of overall survival were 76.9%, 54.5%, and 38.8%, respectively. Eighty-five patients (17.1%) demonstrated CR, 190 (38.3%) demonstrated PR, 168 (33.9%) demonstrated SD, 47 (9.5%) demonstrated progressive disease, and 6 (1.2%) had an inconclusive response as described earlier (Table 3).
The 6-, 12-, and 18-month LC rates were 93.3%, 87.3%, and 84.1%, respectively (Figure). On univariate analysis (UVA), the following were significant for LF (Table 4): dose less than 20 Gy (hazard ratio [HR]: 2.940, 95% confidence interval [CI]: 1.645-5.254, P < .001), tumor size (HR: 1.674, 95% CI: 1.283-2.184, P < .001), and cerebellum/brainstem location vs other (HR: 1.891, 95% CI: 1.020-3.507, P = .0431). NSCLC (HR: 0.333, 95% CI: 0.145-0.766, P = .0097) was associated with better LC. On multivariate analysis (MVA), the following were significant for LF (Table 4): tumor size (HR: 1.696, 95% CI: 1.296-2.220, P < .001) and cerebellum/brainstem location vs other (HR: 1.959, 95% CI: 1.055-3.638, P = .033). Notable variables that were not significant for LF include the following: CI, IDL in %, IDL categorized as less than 70% vs 70% or higher, HI, and the use of WBRT before or concurrent with GK.
Of the lesions analyzed, 61 (12.3%) were documented to be RN. UVA and MVA demonstrated that the following variables were significant for RN (Table 5): CFI (UVA, HR: 0.259, 95% CI: 0.1-0.671, P = .0054; MVA, HR: 0.236, 95% CI: 0.090-0.614, P = .0031) and not smoking (UVA, HR: 1.765, 95% CI: 1.024-3.042, P = .041; MVA, HR: 1.969, 95% CI: 1.138-3.406, P = .015). Notable variables that were not significant for LF include the following: histology of primary disease, IDL in %, IDL categorized as less than 70% vs 70% or higher, and HI. In addition, tumor size was not analyzed with respect to RN.
Our study reports a 12-month LC rate of 87.3%, reinforcing the excellent rates reported in the literature.10 In addition, this study is the first large study to assess response according to the RECIST criteria. We evaluated whether various dosimetric and patient factors were associated with failure and toxicity.
The Impact of CFI on LC
Contrary to expectations, the CFI was not significantly associated with LF (P = .26), in contrast with Soltys et al,7 who described improved LC with less conformal plans, albeit for SRS to the resection bed. Interestingly, increasing values of CFI (ie, less conformal) were associated with decreased RN on this analysis, a finding that Soltys et al did not observe. We hypothesize that because the planning target volume includes both presumed gross tumor as well as a margin that could include normal tissue, the normal tissue would receive a higher dose at lower CFI, increasing the risk of RN.
Taken together, our results suggest that less conformal planning may reduce the risk of RN without any associated increase in LF. However, other factors, including gradient index, likely need to be assessed when determining optimal treatment plans.11 One explanation is that more conformal plans are seen for larger brain metastases, which are at higher risk of RN. In addition, to get a more conformal plan, the tumor volume receiving a higher than prescription dose may also be higher, resulting in a higher rate of RN. Further exploration of this issue is needed.
The Impact of HI on LF and RN
Importantly, HI was not significantly associated with either LF or RN. Per RTOG 90 to 05, the dose in GK is prescribed to the 50% to 60% IDL. Our finding agrees with this RTOG trial in that HI of 2 or less was not associated with toxicity. The initial report did suggest that dose inhomogeneity could explain the improvement in LC seen in GK compared with LINAC-based units; however, the final report failed to confirm this finding. In theory, the internal hot spots generated may boost the central hypoxic, radioresistant portion of the tumor, resulting in better LC.6 However, our finding suggests that not only does treating to higher IDLs not sacrifice either LC or toxicity while reducing treatment time, but also that the minimum dose, rather than the maximum dose, is most important for tumor control irrespective of IDL. This benefit is notable for patients with multiple metastases and who are uncomfortable being in treatment for hours. We are exploring the significance of the gradient index for LF and RN in another study.
Other Factors and Their Impact on LC
As expected, lower prescription doses and higher maximum tumor diameters were associated with LF.12,13 Interestingly, NSCLC predicted for better LC vs other primary cancers (P = .0097), although there was no correlation between smoking and LF (P = .38). The significance for NSCLC and lower prescription doses disappears on MVA. Melanoma or renal cell carcinoma primary tumors (considered radioresistant) were not significantly predictive but were suggestive of LF (P = .065). Indeed, Lwu et al14 demonstrated excellent LC rates of 75% and 91% for BMet from melanoma or renal cell carcinoma primary tumors, and we agree that SRS remains effective for traditionally radioresistant primary cancers. BMet located in the brainstem or cerebellum was significantly predictive of LF as well (P = .043). However, LC when brainstem metastases are treated with SRS is still excellent, and this finding should not preclude SRS for brainstem or cerebellar metastases.15
Other Factors and Their Impact on RN
Another positive association for increased rates of RN was having no history of smoking. Interestingly, being a former smoker was not associated with RN when compared with never smokers as well as current smokers. In addition, the primary cancer (and NSCLC in particular) had no association with RN. These findings suggest that any history of smoking (current or past) may be protective against RN and that quitting smoking did not change a patient's risk of RN. We were unable to find any other study that commented on smoking and SRS. However, this study was not designed to investigate RN, and we are currently looking at patient predictive factors for RN in another study.
Comments on Study Design
The strengths of this study lie in the large sample size, the use of RECIST criteria, and the stipulation that we analyze only those BMet treated with GK for the first time. The large sample size gives this study sufficient power to justify our conclusions. We used RECIST criteria to more rigorously define tumor progression. We also decided to include only those BMet treated with GK for the first time to reduce the potential confusion about total dose as well as about following outcomes on MRI.
The main limitations of this study was its retrospective nature and the inherent selection biases of this study design. This study also reports only a single institution's experience. A prospective study would be ideal and provide more accurate data on prognostic factors for GK to BMet.
GK for BMet results in excellent LC and a low overall rate of toxicity. This analysis demonstrated that there is no significant difference between high and standard IDLs in LC and RN in GK for BMet. This finding suggests that not only can treatment times be reduced and patient comfort be increased, but also that clinicians may treat to higher IDLs without fear of sacrificing control or increasing toxicity. In addition, although less conformal plans were shown to decrease the risk of RN, this needs further study and should not be the standard for planning.
Kevin Shiue was awarded a 2011 American Cancer Society Joseph and Jeanette Silber Student Research Fellowship to support his participation in this study. Dr Barnett has the following associations with Monteris Medical: consultancy, payment for lectures and manuscript preparation (not this manuscript) and development of educational presentations, and stock options. Dr Vogelbaum is a consultant for Merck, Pharmicokinesis, and Neuralstem and holds a patent with Infuseon Therapeutics. Dr Weil was supported in part by grant W81XWH-062 to 0033 from the US Department of Defense Breast Cancer Research Program. Dr Angelov has received payment for serving on the speakers' bureau of BrainLab. Dr Neyman is a consultant for Elekta AB and received payment for lectures for Elekta AB. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.
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Historically, normalization (minimum 3-dimensional isodose prescription line that encompasses the entire lesion) has varied significantly from various radiosurgery delivery devices. Gamma Knife (GK) planning techniques place the edge of the collimator field size at the periphery of the lesion; thus, the normalization is approximately 50%. This is the same for any radiation field when you calculate the dose at a field edge because scattered radiation can only come from tissue central to the periphery. The advantage of low normalization is conformal dose distributions and higher mean doses. The disadvantage is significant dose inhomogeneity and longer treatment times. Linear accelerator-based systems have the luxury of larger field sizes; thus, normalization can be high. If multiple lesions are going to be treated with the GK, normalizing the plan to higher isodose normalization values will allow for more rapid delivery along with the reduction of integral doses distributed to large volumes of brain tissue. The chance of tumor control is a statistical probability controlled by the minimum dose delivered to the tumor clonogens. Thus, the results of this study are not surprising and might help to lead to discussions for the reform of the classic low normalization for GK treatments.
Jay S. Loeffler
When in the late 80s and early 90s gamma knife surgery began to propagate around the world, our community accepted a certain number of guidelines or dogma as basic rules. That dose rate does not change safety efficacy and that toxicity events are related to the energy delivered directly to normal tissues outside the target are widely accepted concepts, as is the notion that the optimum prescription isodose line is 50%. As a matter of fact, the analysis of dose distribution profile, when using a single 4 mm isocenter, shows that the isodose where the dose fall-off is steepest, is close to the 50% level (actually between 60 and 50%). When a complex multi-isocentric dose plan is considered, the best slope is frequently somewhere around 40 and 50%. In theory it thus makes sense to make the periphery of the target fit with the 50% isodose line of the plan, as long as this is the point offering the advantage of a rapid decrease of dose outside (better gradient index) and a rapid increase of the dose inside.4,8 In the meantime, mainly due to different dose distribution profiles, the LINAC community has been using a much higher reference isodose at the periphery of the target. It is of importance to note that one of the major advantages of radiosurgery in brain metastases is the very high local control in the absence of whole brain radiotherapy5,6 as opposed to resection, which requires adjunctive local radiotherapy to the tumor bed in order to avoid a local recurrence.7 This is supposed, according to Kondziolka et al (personal communication), to be due to the radiation delivered to the immediate vicinity of the lesion (penumbra phenomenon) at the site at which the infiltrating disease is taking place. The use of a much lower isodose line than 50% at the margin would then lead to a dramatic increase of the maximum dose and total energy delivered to the target and could thus increase the efficacy (for the use of the same dose at the marginal isodose). In addition the use of a much higher isodose at the margin would increase the total energy delivered to normal surrounding structures and could lead to a higher probability of toxicity. On the other hand, the use of a much higher isodose at the margin would also decrease the total energy delivered to the lesion itself (with a theoretical higher risk of failure). However, in spite of these physical facts, the authors have failed, in this retrospective single center study, to find any significant difference between high and standard isodose lines in local control and radiation necrosis risk. Of course these conclusions apply specifically to the conditions of practice in this center (with regards to dose prescription & WBRT policy). The authors report using the “Recommendations from the Radiation Therapy Oncology Group 90 to 05 clinical trial” for dose selection in this series.10 However some lesions were prescribed as low as 10 Gy! Compared to dose policy in recent papers from numerous institutions, these old recommendations would appear to be rather conservative. The higher rate of failures for lesions treated with lower doses, especially for doses lower than 20 Gy, fits with this interpretation.8 Here the Index of Shaw et al9 is used for conformity (PIV/TV), which is proving to be a predictor for radiation necrosis both in uni- and multivariate analysis. This old index is quite a crude instrument, as mentioned by the authors. Globally here it seems to indicate that this is due to poor selectivity, meaning overtreatment of the target, and not poor conformity, which may be misinterpreted as insufficient coverage. A more meaningful analysis of this issue would require separate evaluation of coverage, selectivity and gradient.
According to the authors 259 of the 496 lesions (52%) were treated with WBRT! This is a major bias, which may significantly affect the conclusions of the authors. The tendency nowadays is to try to limit the use of WBRT, in order to limit its neurotoxicity in the absence of demonstrated clinical benefit.1-3,5
It would therefore be, as acknowledged by the authors, of the utmost importance to prospectively test the impact of doseplanning parameters as higher marginal isodoses, in patients free of WBRT.
1. Aoyama H, Shirato H, Tago M, et al.. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483–2491. View Full Text | PubMed | CrossRef
2. Aoyama H, Tago M, Kato N, et al.. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys. 2007;68(5):1388–1395. PubMed | CrossRef
3. Chang EL, Wefel JS, Hess KR, et al.. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol. 2009;10(11):1037–1044. PubMed | CrossRef
4. Hayashi M, Chernov M, Tamura N, et al.. Gamma knife robotic microradiosurgery for benign skull base meningiomas: tumor shrinkage may depend on the amount of radiation energy delivered per lesion volume (unit energy). Stereotact Funct Neurosurg. 2011;89(1):6–16. PubMed | CrossRef
5. Kocher M, Soffietti R, Abacioglu U, et al.. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134–141. PubMed | CrossRef
6. Muacevic A, Wowra B, Siefert A, Tonn JC, Steiger HJ, Kreth FW. Microsurgery plus whole brain irradiation versus Gamma Knife surgery alone for treatment of single metastases to the brain: a randomized controlled multicentre phase III trial. J Neurooncol. 2008;87(3):299–307. View Full Text | PubMed | CrossRef
7. Patchell RA, Tibbs PA, Regine WF, et al.. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280(17):1485–1489. View Full Text | PubMed | CrossRef
8. Niranjan A. Conformity index for radiosurgery. Neurosurgery. 2010;67(2):E521. View Full Text | PubMed | CrossRef
9. Shaw E, Kline R, Gillin M, et al.. Radiation Therapy Oncology Group: radiosurgery quality assurance guidelines. Int J Radiat Oncol Biol Phys. 1993;27(5):1231–1239. PubMed | CrossRef
10. Shaw E, Scott C, Souhami L, et al.. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291–298. PubMed | CrossRef
1. What is the impact of treating at a higher than the typical 50% isodose line (IDL) when using Gamma Knife to treat single brain metastasis?
A. Shorter treatment time
B. Lower chance of local recurrence
C. Higher chance of radiation necrosis
D. Increased steroid dependence
E. Increased local control rate
2. According to recent guidelines for the treatment of brain metastases, Level 1 evidence shows a survival benefit for patients with a single brain metastasis treated with stereotactic radiosurgery (SRS) + whole brain radiation therapy (WBRT) compared to what treatment modality(ies)?
A. WBRT alone
B. SRS alone
C. Resection alone
D. Resection + SRS
E. Resection + WBRT
3. According to the Response Evaluation Criteria In Solid Tumors (RECIST), what is the criterion for local treatment failure after radiotherapy of brain metastases?
A. ≥ 10% increase in the lesion
B. ≥ 20% increase in the lesion
C. ≤ 20% decrease in the lesion
D. ≤ 10% decrease in the lesion
E. No change in the lesion
Brain metastases; Isodose line; Radiation necrosis; Radiosurgery
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