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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 3  |  Page : 575-580

Volume changes during head-and-neck radiotherapy and its impact on the parotid dose – A single-institution observational study


Department of Radiotherapy, Apollo Cancer Institute, Chennai, Tamil Nadu, India

Date of Submission12-Aug-2019
Date of Decision17-Oct-2019
Date of Acceptance30-Dec-2019
Date of Web Publication18-Jul-2020

Correspondence Address:
Bhargavi Ilangovan
64 G, SR Dream Bungalow, Gowri Nagar, Mugalivakkam, Chennai - 600 125, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_589_19

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 > Abstract 


Aims: This study aims at assessing the volume changes that occur in the targets (gross tumor volume and planning target volume [PTV]) and the organs at risk in squamous cell carcinoma of the head and neck during radiotherapy and assessing the dose changes that occur as a result of them.
Settings and Design: This was a prospective observational study in a tertiary care center after obtaining the appropriate scientific and ethics committee clearance.
Subjects and Methods: Forty-five patients diagnosed with squamous cell carcinoma of the head and neck, who were treated with intensity-modulated radiotherapy in the time period from March 2018 to May 2019, were enrolled in the study. A planning computed tomography (CT) scan (CTplan) was done for all patients, followed by scans after 15 fractions (CT15) and after 25 fractions (CT25). The volume changes and the subsequent dose changes were assessed and recorded.
Statistical Analysis Used: Data entry was done in MS Excel spreadsheet. The continuous variables were expressed as mean + standard deviation. The comparison of normally distributed continuous variables was done by paired t-test. Data analysis was done by SPSS (Statistical Package for the Social Sciences) version 16.0. P < 0.05 was considered statistically significant. A multivariate linear regression model was constructed to study the correlation between mean dose to the parotid glands and the other variables. All statistical modeling and analysis were done using SAS (Statistical Analysis Software) version 9.4.
Results: Of the 45 patients, 25 were male and 20 were female. The majority of the patients had malignancies in the oral cavity (16) and hypopharynx (14). Most of them had Stage III/IV (AJCC v 8) disease (41). There were a 36% decrease in the PTV-high risk (PTV-HR) volume and a 6.05% decrease in the PTV-intermediate risk (PTV-IR) volume CT15. In CT25, the volume decrease in the PTV-HR and the PTV-IR was 47% and 9.06%, respectively. The parotid glands also underwent a reduction in their volume which has been quantified as 21.7% and 20.9% in the ipsilateral and contralateral parotids in CT15 and 36% and 33.6% in CT25, respectively. The D2 (dose received by 2% of the volume) and D98 (dose received by 98% of the volume) of the PTV-IR showed changes of +3.5% and –0.2% in CT15 and + 4.6% and –0.31% in CT25, respectively. The homogeneity index and conformity number of the PTV-IR changes by 0.03 and 0.08 in CT15 and by 0.04 and 0.12 in CT25, respectively. The mean dose to the ipsilateral parotid gland increased by 14% in CT15 and 19% in CT25. The mean dose to the contralateral parotid gland increased by 17% in CT15 and 25% in CT25.
Conclusion: The dose to the parotid glands increases as a result of the changes that occur during the course of radiation. The changes are significant after 15 fractions of radiation. A replanning at this juncture might be considered to reduce the dose to the parotid glands.

Keywords: Head-and-neck radiotherapy, intensity-modulated radiotherapy, parotid glands, volume changes


How to cite this article:
Ilangovan B, Venkatraman M, Balasundaram S. Volume changes during head-and-neck radiotherapy and its impact on the parotid dose – A single-institution observational study. J Can Res Ther 2020;16:575-80

How to cite this URL:
Ilangovan B, Venkatraman M, Balasundaram S. Volume changes during head-and-neck radiotherapy and its impact on the parotid dose – A single-institution observational study. J Can Res Ther [serial online] 2020 [cited 2020 Aug 12];16:575-80. Available from: http://www.cancerjournal.net/text.asp?2020/16/3/575/289976




 > Introduction Top


Head-and-neck malignancies constitute the third most common tumors in India.[1] Radiation therapy forms an important modality in the management of head-and-neck malignancies. The increased rate of organ preservation has made radiotherapy an inevitable treatment modality in these cancers.[2],[3] During radiotherapy, the patient's anatomy undergoes changes in the form of decrease in the tumor volume, nodal volume, weight loss, and the changes in parotid volume.[4] As a result of these, the mean dose to the parotid is generally more than what is calculated based on the treatment planning computed tomography (CT). This study aims to quantify the abovementioned volume changes, the subsequent dose changes, and their effect on the parotid gland dose.


 > Subjects and Methods Top


This is a prospective nonrandomized observational clinical study. This was conducted in a tertiary care oncology hospital. The study was commenced after clearance from the hospital's scientific and ethics committee.

The study involved 45 patients diagnosed with squamous cell carcinoma of the head and neck undergoing radiotherapy with intensity-modulated radiotherapy with a Karnofsky Performance Status ≥70 and with Stage T2a–T4, N0–N3, and M0. Early-stage diseases which would warrant small fields or ipsilateral neck fields were excluded. Radiotherapy preparation consisted of immobilization using a neck rest and thermoplastic mask. A CT scan (CTplan) of the head-and-neck region from the base of the skull to the superior mediastinum was obtained in 3 mm slice thickness. The CT scan images were transferred to the Oncentra treatment planning system. The images were imported, and the gross tumor volumes (GTVs) and clinical target volumes (CTVs, comprising CTV primary and the nodal volumes) were contoured in axial images. A planning target volume (PTV) expansion of the GTV and the CTV was created (GTV with a 3 mm margin to create the PTV-HR and CTV with a 5 mm margin to create the PTV-IR). The organs at risk (OARs such as the parotids, spinal canal, and mandible) were also contoured.

The patient images and contours were then given for radiotherapy planning. A dose of 66 Gy in 33 fractions was delivered to the PTVHR and a dose of 59.4 Gy in 33 fractions was delivered to the PTVIR. Dose constraints of mean dose <26 Gy to the bilateral parotids and <20 Gy if only one parotid can be spared and a Dmax of 45 Gy to the spinal canal were imposed. The plans were evaluated by visual analysis of the isodose lines and evaluation of the dose-volume histograms. Once the plan was acceptable, it was approved, and the details were exported for treatment delivery. All patients received concurrent weekly cisplatin (40 mg/m2).

A follow-up CT was done at the end of 15 fractions (CT15) and at the end of 25 fractions (CT25) using the same abovementioned protocols. The follow-up CT images were registered with the planning CT images by the mutual information method. The structure sets in the CTplan were transferred to the CT15 and CT25.

The structures including the GTV, CTV, and OARs were manually modified in all axial slices, by the same physician according to the changes in the body, primary tumor, nodes, nodal volumes, and the parotids, thereby reducing the interobserver variations. PTV-HR and PTV-IR were generated based on the same expansion margins as for the CTplan. The volume changes in the PTV-HR, PTV-IR, and ipsilateral (iParotid) and contralateral (cParotid) parotids were measured and documented. By transferring the primary structure sets, and then modifying them rather than recontouring, the subjective errors while contouring were minimized. The optimized beam setup of the original plans done on CTplan was then imported onto CT15 and CT25 which then had the modified structure sets. In CT15 and CT25, reference marks were kept indicating the isocenter position. Hence, it was possible to align the isocenter to match that in the original plan using the beam modeling tool and recalculate the dose for the structure sets in CT15 and CT25. This plan depicted the doses the structures would receive if the same primary plan was to be executed over the modified volume.

The D2(dose received by 2% of the volume) and D98 (dose received by 98% of the volume) were measured for the tumor volumes; Dmean (mean dose) for the parotids and Dmax (maximum dose), D2cc (Dose to 2cc of the spinal canal) for the spinal canal and Dmax for the mandible were observed and documented in each of the plans. The changes in the low-dose volumes and the high-dose volumes were derived in each follow-up scan. The homogeneity and conformity indices were calculated. Homogeneity index (HI) was calculated using the following formula:

HI= (D2-D98/D50) × 100[5]

D2= dose received by 2% of the volume,

D98= dose received by 98% of the volume,

D50= dose received by 50% of the volume.

The conformity number (CN) was calculated using the following formula:

CN= (VTD/V) × (VTD/VD)[6]

CN= Conformity number,

VTD= Volume of the target covered by the isodose line,

VD= total volume covered by the isodose line,

V = Volume of the target.

Data entry was done in MS Excel spreadsheet. The continuous variables were expressed as mean + standard deviation. The comparison of normally distributed continuous variables was done by paired t-test. Data analysis was done by IBM SPSS Statistics for Windows, version 16 (IBM Corp., Armonk, N.Y., USA). P < 0.05 was considered statistically significant. A multivariate linear regression model was constructed to study the correlation between mean dose to the parotid glands and the other variables. All statistical modeling and analysis were done using SAS Institute Inc 2013. SAS/ACCESS® 9.4.


 > Results Top


A total of 45 patients with squamous cell carcinoma of the head-and-neck region were enrolled in this study. Their characteristics are shown in [Table 1].
Table 1: Patient characteristics

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There was a statistically significant reduction observed in the volumes of the PTV-HR, PTV-IR, and ipsilateral and contralateral parotid glands. The change was significant even after 15 fractions [Table 2].
Table 2: Volumes with significant changes on CT15 and CT25 in relation to CTplan

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The subsequent dose changes were assessed in the form of minimum and maximum doses, HI, and conformity index. The D2 of the PTV-HR and PTV-IR increases with statistical significance. The D98 of the PTV-IR and the PTV-HR showed a decrease in the dose without statistical significance. The changes were significant even at the end of 15 fractions [Table 3].
Table 3: Averaged dose-volume parameters on CTplan, CT15, and CT25 for target volumes

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The volume of the PTV-IR covered by the prescription isodose line showed a statistically significant decrease. However, the total volume covered by the prescription isodose line showed a statistically significant increase, suggesting that more than intended normal tissue was being irradiated [Table 4].
Table 4: Averaged volumes covered by the prescription isodose line on CTplan, CT15, and CT25 for PTV-IR

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There was a significant increase in the mean dose to the parotid glands, and the Dmax to the spinal canal and mandible also showed a significant increase in CT15 and CT25[Table 5].
Table 5: The mean dose changes of organs at risk in CTplan, CT15, and CT25

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A multivariate linear regression model was constructed to study the correlation between cParotid mean dose, PTV-IR VD, PTV-IR, and stage. The independent variables were chosen based on the best fit for the model. The parameter estimates for the intercept and PTV-IR VD were found to be statistically significant. The model shows a positive correlation between the dependent variable and PTV-IR VD and stage and a negative correlation between the dependent variable and PTV-IR. Based on the model, a 1% increase in PTV-IR VD would cause an increase of 0.20% in the cParotid Dmean value. To further study the degree of dependence between the dependent variable and the independent variables, a Pearson and Spearman correlation tests were performed. The tests showed that cParotid mean has the most dependence on PTV-IR VD. The Pearson and Spearman correlation coefficients are listed below.

Similarly, another regression model was built to study the correlation between iParotid Dmean and the other variables PTV-IR, PTV-IR VD, PTV-IR VTD, gender, and age. The parameter estimates were found to be statistically significant for all of the independent variables, except age. The model exhibits a positive correlation between iParotid Dmean and the independent variable PTV-IR VD. Based on the model, a 1% increase in PTV-IR VD would cause an increase of 0.10% in the iParotid Dmean value.


 > Discussion Top


The aim of IMRT is to achieve tumor control while sparing the adjacent normal structures. In other words, it increases the therapeutic index by lowering the normal tissue complication probability. This has been tested and proven in studies which have shown the positive effect of IMRT in reducing the rates of Grade 2 xerostomia in patients with head-and-neck cancers undergoing radiotherapy with IMRT.[7] However, the decrease in the volume of the PTV-HR, PTV-IR, parotid glands, and the other positional changes occurring throughout the course of radiotherapy results in delivering more than planned dose to the adjacent normal tissues.[8]

In our study, there were a 36% decrease in the PTV-HR volume and a 6.05% decrease in the PTV-IR volume at the end of 15 fractions. After 25 fractions, the volume decrease in the PTV-HR and the PTV-IR was 47% and 9.06%, respectively. The PTV-IR volume change in our study is less than that reported in earlier studies.[9] This could be because majority of the patients included in this study had laryngopharynx and oral cavity malignancies. The PTV-IR changes in most of them were due to the reduction in the lateral separation of the neck, rather than gross changes in the PTV-HR. The PTV-HR changes did not alter the CTV or the PTV-IR as the regions harboring subclinical diseases, such as the neck nodal regions, did not undergo much change. The PTV-HR volume changes, however, are comparable with other earlier studies.[10],[11]

The parotid glands underwent a reduction in their volumes, which has been quantified as 21.7% and 20.9% in the ipsilateral and contralateral parotids at the end of 15 fractions and 36% and 33.6% in the ipsilateral and contralateral parotids at the end of 25 fractions. As a result of these abovementioned changes in the PTV-HR, PTV-IR, and the parotid glands, there occurred a change in the dose delivered to the target volumes and normal structures [Figure 1].
Figure 1: (a-c) Coronal images of the CTplan, CT15, and CT25showing parotid volume changes and the VTD increase

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The maximum dose to the PTV-HR and the PTV-IR (as recorded as the dose to 2% of the target volume) showed an increase and the minimum dose (as recorded as the dose 98% of the target volume) showed a nonsignificant decrease. The total volume irradiated by the prescription isodose line increased as the volume of the PTV-IR decreased. As a result of these changes, the plans were more inhomogeneous and less conformal. Similar results have been reported by studies earlier[12] [Figure 2].
Figure 2: Dose-volume histogram of the parotid gland dose in the three computed tomography scans

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This increases the volume irradiated by the prescription isodose line as a result of the PTV-IR volume changes and the movement of the parotid into this area coupled with the parotid gland's volume changes increases the dose to the parotid glands. The rate of xerostomia might increase as the mean doses increases. There are several studies which have applied NTCP (normal tissue complication probability) models to see the correlation between the two, suggesting that keeping the mean dose of the parotid as low as possible without compromising the target coverage is prudent.[13],[14],[15],[16]

The quality of life will be better if we were to reduce the rate of incidence of xerostomia.[17],[18] Although recovery of salivary function has been reported, it is prudent to keep the dose to the minimum without compromising on the tumor control.

Studies assessing the role of weekly IMRT adaptive planning have been done and have concluded that these strategies improve PTV coverage and reduce the normal tissue doses.[19]

While analyzing the kinetics of these changes, it has been found in this study, as has been shown in multiple other studies, that the changes are statistically significant after 15 fractions. This is shown by significant volume and dose changes CT15. This is similar to the studies in the literature.[9],[20],[21] Bhide et al. analyzed weekly and concluded that the changes were significant in the second week. Beltran et al. and Bhandari et al. also made similar assessments. In a study by Schwartz et al., they suggested that the changes were significant during the 3rd and 4th weeks of radiotherapy.[22]

This has been said to be because the more sensitive acinar cells succumb to radiotherapy in the early weeks and the less sensitive cells remain with smaller volume changes thereafter.[23] In general, a replanning at this juncture might lead to improved preservations of the critical structures and thereby help us achieve the goal with which we started the radiotherapy treatment planning. The changes in the dose to the spinal canal and the mandible were similar to other studies and were within their tolerance levels.[20]


 > Conclusion Top


It was observed that the target volumes and the normal structures underwent changes during the course of radiotherapy. There was a reduction in the volumes of the GTV, CTV, and the parotid glands. The subsequent dose changes were in the form of increase in the maximum dose to the PTV-HR and PTV-IR and decrease in the minimum dose. The total volume covered by the prescription isodose line also increased leading to irradiation of more adjacent normal tissue. The dose changes to the normal structures were in the form of increase in the mean dose to the parotid glands and the maximum dose to the mandible and spine. Of the normal structures analyzed, the increase in the mean dose to the parotid glands may reflect as an increase in the rate of incidence of xerostomia. Although other variables also have been studied, such as the mean dose to the soft palate and submandibular glands, the mean dose to the parotid gland remains a factor that can be controlled assessment of the volume changes.[24] These changes are statistically significant even after 15 fractions of radiation. Hence, a replan at this juncture might be beneficial in reducing long-term toxicities. Furthermore, the use of models[25] to choose the patients who might benefit from the replanning may help in optimal use of the technique.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424.  Back to cited text no. 1
    
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Fiorentino A, Caivano R, Metallo V, Chiumento C, Cozzolino M, Califano G, et al. Parotid gland volumetric changes during intensity-modulated radiotherapy in head and neck cancer. Br J Radiol 2012;85:1415-9.  Back to cited text no. 4
    
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van't Riet A, Mak AC, Moerland MA, Elders LH, van der Zee W. A conformation number to quantify the degree of conformality in brachytherapy and external beam irradiation: Application to the prostate. Int J Radiat Oncol Biol Phys 1997;37:731-6.  Back to cited text no. 6
    
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Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): A phase 3 multicentre randomised controlled trial. Lancet Oncol 2011;12:127-36.  Back to cited text no. 7
    
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Patel PN, Goyal S, Shah A, Gohel M, Suryanarayana U. Prospective study of sequential volumetric changes of parotid gland in early oropharyngeal carcinoma patients treated by intensity-modulated radiation therapy: An institutional experience. South Asian J Cancer 2018;7:55-7.  Back to cited text no. 8
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Bhide SA, Davies M, Burke K, McNair HA, Hansen V, Barbachano Y, et al. Weekly volume and dosimetric changes during chemoradiotherapy with intensity-modulated radiation therapy for head and neck cancer: A prospective observational study. Int J Radiat Oncol Biol Phys 2010;76:1360-8.  Back to cited text no. 9
    
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Bando R, Ikushima H, Kawanaka T, Kudo T, Sasaki M, Tominaga M, et al. Changes of tumor and normal structures of the neck during radiation therapy for head and neck cancer requires adaptive strategy. J Med Invest 2013;60:46-51.  Back to cited text no. 10
    
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Geets X, Tomsej M, Lee JA, Duprez T, Coche E, Cosnard G, et al. Adaptive biological image-guided IMRT with anatomic and functional imaging in pharyngo-laryngeal tumors: Impact on target volume delineation and dose distribution using helical tomotherapy. Radiother Oncol 2007;85:105-15.  Back to cited text no. 11
    
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Huang H, Lu H, Feng G, Jiang H, Chen J, Cheng J, et al. Determining appropriate timing of adaptive radiation therapy for nasopharyngeal carcinoma during intensity-modulated radiation therapy. Radiat Oncol 2015;10:192.  Back to cited text no. 12
    
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Lee TF, Chao PJ, Wang HY, Hsu HC, Chang P, Chen WC. Normal tissue complication probability model parameter estimation for xerostomia in head and neck cancer patients based on scintigraphy and quality of life assessments. BMC Cancer 2012;12:567.  Back to cited text no. 13
    
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Castelli J, Simon A, Rigaud B, Lafond C, Chajon E, Ospina JD, et al. A Nomogram to predict parotid gland overdose in head and neck IMRT. Radiat Oncol 2016;11:79.  Back to cited text no. 14
    
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Wu Q, Chi Y, Chen PY, Krauss DJ, Yan D, Martinez A. Adaptive replanning strategies accounting for shrinkage in head and neck IMRT. Int J Radiat Oncol Biol Phys 2009;75:924-32.  Back to cited text no. 15
    
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Houweling AC, Philippens ME, Dijkema T, Roesink JM, Terhaard CH, Schilstra C, et al. A comparison of dose-response models for the parotid gland in a large group of head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 2010;76:1259-65.  Back to cited text no. 16
    
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Memtsa PT, Tolia M, Tzitzikas I, Bizakis J, Pistevou-Gombaki K, Charalambidou M, et al. Assessment of xerostomia and its impact on quality of life in head and neck cancer patients undergoing radiation therapy. Mol Clin Oncol 2017;6:789-93.  Back to cited text no. 17
    
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Castelli J, Simon A, Louvel G, Henry O, Chajon E, Nassef M, et al. Impact of head and neck cancer adaptive radiotherapy to spare the parotid glands and decrease the risk of xerostomia. Radiat Oncol 2015;10:6.  Back to cited text no. 18
    
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Aly F, Miller AA, Jameson MG, Metcalfe PE. A prospective study of weekly intensity modulated radiation therapy plan adaptation for head and neck cancer: Improved target coverage and organ at risk sparing. Australas Phys Eng Sci Med 2019;42:43-51.  Back to cited text no. 19
    
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Beltran M, Ramos M, Rovira JJ, Perez-Hoyos S, Sancho M, Puertas E, et al. Dose variations in tumor volumes and organs at risk during IMRT for head-and-neck cancer. J Appl Clin Med Phys 2012;13:3723.  Back to cited text no. 20
    
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Beetz I, Schilstra C, Van Der Schaaf A, van den Heuvel ER, Doornaert P, van Luijk P, et al. ALLEGRO project NTCP models for patientrated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: The role of dosimetric and clinical factors q. Radiother Oncol 2012;105:1016.  Back to cited text no. 24
    
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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