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ORIGINAL ARTICLE
Ahead of print publication  

Dosimetric comparative study of conformal radiation techniques in patients with glioblastoma multiforme


1 Department of Radiological Physics and Bio-Engineering, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, India
2 Department of Physics, Baba Ghulam Shah Badshah University, Rajouri, Jammu, Jammu and Kashmir, India

Date of Submission07-Mar-2022
Date of Decision02-May-2020
Date of Acceptance05-Apr-2022
Date of Web Publication24-Aug-2022

Correspondence Address:
Sajad Ahmad Rather,
Department of Radiological Physics and Bio-Engineering, Sher-I-Kashmir Institute of Medical Sciences, Srinagar
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrcr.jrcr_19_22

  Abstract 

Purpose: The purpose of the current study is to determine whether patients diagnosed with glioblastoma multiforme (GBM) who underwent radiotherapy (RT) using intensity-modulated RT (IMRT) technique were benefitting from this highly conformal treatment in terms of doses received by planning target volume (PTV) and organs at risk (OARs) in comparison to three-dimensional conventional RT (3DCRT). Materials and Methods: Twelve patients treated with IMRT for GBM were selected for dosimetric comparison with 3DCRT. The prescribed dose was 60 Gy in 30 fractions and seven non-coplanner beams were used in IMRT to cover 95% of target volume. The irradiated patients of GBM were retrieved and replanned with 3DCRT techniques. Dosimetric comparison was done by performing two plans for the same patient; prescription dose and normal tissue constraints were identical for both plans. The dose–volume histograms of target volumes and OAR, dose conformity, and dose homogeneity with 3DCRT and IMRT planning were compared. Statistical analysis was performed to determine the differences. Results: The mean conformity index was 0.99 ± 0.001 for IMRT and 0.97 ± 0.002 for 3DCRT, P = 0.001. The mean homogeneity index was 1.03 ± 0.02 for IMRT and 1.06 ± 0.009 for 3DCRT, P = 0.003, which is statistically significant. The IMRT technique enables dose reduction of normal tissues including brainstem (Dmean by 33.78 ± 5.34 and Dmax 51.84 ± 4.43), optic chiasm (Dmean by 36.92 ± 1.99 and Dmax 44.61 ± 3.72), left optic nerve (Dmean by 28.97 ± 6.51 and Dmax 46.08 ± 10.58), right optic nerve (Dmean by 31.93 ± 11.68 and Dmax 44.63 ± 13.54), left eye (Dmean by 18.66 ± 8.92 and Dmax 37.43 ± 13.47), right eye (Dmean by 14.40 ± 4.87 and Dmax 40.37 ± 11.37), left lens (by Dmax 5.45 ± 1.85), and right lens (Dmax 5.07 ± 0.63). Conclusion: The IMRT provides a real dosimetric advantage, especially for normal brain tissue, and in terms of target coverage. It allows treatment of tumors while respecting OARs' dose constraints. The IMRT technique shows significant advantage in PTV coverage, dose homogeneity, and conformity. In IMRT, the coverage is better where PTV was overlapping with critical OARs.

Keywords: Glioblastoma multiforme, intensity-modulated radiotherapy, three-dimensional conventional radiotherapy



How to cite this URL:
Rather SA, Khan AA, Mir FA, Haq M M. Dosimetric comparative study of conformal radiation techniques in patients with glioblastoma multiforme. J Radiat Cancer Res [Epub ahead of print] [cited 2022 Dec 4]. Available from: https://www.journalrcr.org/preprintarticle.asp?id=354439


  Introduction Top


High-grade gliomas account for majority of primary central nervous system tumors and are infiltrative tumors with microscopic disease extending into the adjacent brain. They are divided into anaplastic gliomas including anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma.

Malignant gliomas are histologically heterogeneous and invasive tumors that are derived from glia. The World Health Organization classifies astrocytomas on the basis of histological features into four prognostic grades: Grade I (pirocytic astrocytoma), Grade II (diffuse astrocytoma), Grade III (anaplastic astrocytoma), and Grade IV (glioblastoma).[1] Glioblastoma accounts for approximately 60%–70% of malignant gliomas, also known as glioblastoma multiforme (GBM).

The multimodality treatment with maximal surgical resection followed by adjuvant radiotherapy (RT) and chemotherapy represents the standard approach to the treatment of glioblastoma (GBM).[2] In addition to surgery, RT remains the cornerstone of treatment.[3] With ongoing improvements in the technical delivery of RT, there is clinical benefit for patients with both reduced short and late toxicity. In addition, the patients are living longer and a greater proportion are remaining functionally well until late in the course of their disease. The standard dose is 60 Gy in 30 fractions. The difficulty of GBM RT is to spare organs at risk (OARs) such as brainstem, optic chiasm, optic nerves, lens, and cochlea. The primary goal in external beam RT treatment is to accurately deliver prescribed dose to the target while minimum dose to the OARs (while sparing the normal organs, which are closely situated to the tumor).

Modern RT techniques including intensity-modulated radiation therapy (IMRT) allow better conformity dose to the target with a subsequent decrease in treatment-related complications. IMRT is a high-precision RT that uses computer-controlled linear accelerators to provide precise radiation doses for malignancies in advanced patterns. IMRT allows delivery of high dose of radiation to the target while sparing surrounding critical structures. It is produced by delivering multiple beamlets of radiation, from many angles incident on a target. These individual beamlets are dynamically shaped so that different areas within the target can receive different doses of radiation simultaneously. It far better achieves the standard goals of radiation therapy: to deliver a high dose of radiation to the target and spare the normal tissues, than conformal RT. As IMRT allows better target coverage and dose conformity with complex, irregular shapes, it is also able to reduce toxicity by achieving a better dose gradient between the target and normal tissues.[4],[5],[6],[7]

Postoperative RT is absolutely essential for high-grade glioma. With the technical advances in RT, the use of intensity-modulated radiation therapy (IMRT) and volumetric-modulated arc therapy for the radiation of high-grade glioma is increasingly common as a substitute for three-dimentional radiotherapy (3DCRT).[8] Several studies have reported that IMRT can achieve high conformity for the target while reducing the dose to OARs, compared with 3DCRT.[9],[10],[11],[12] Wagner et al.[9] reported the dosimetric comparison of IMRT and 3DCRT plans for 14 consecutive patients with malignant glioma, and they mentioned that if the planning target volume (PTV) is near an OAR, the PTV coverage for IMRT is more acceptable than that for 3DCRT. Lorentini et al.[10] reported that the clinical dosimetric scenario could benefit the most from an IMRT plan versus a 3DCRT plan for 17 patients with glioblastoma, and they reported that the higher the number of PTV-OARs overlaps, IMRT provides the better target coverage compared to 3DCRT plan.

The three-dimensional conformal radiation therapy (3DCRT) allows manual optimization of beam orientation, beam weighting, and beam eye view shaping. However, the problem of dose inhomogeneity and suboptimal conformity to the concave target volume is still unresolved. Intensity-modulated radiation therapy (IMRT), compared with 3DCRT, provides more freedom with allowing dose intensity modulation within each individual beam. As a result, the dose distribution can conform to the target to an extent that was not reached previously. In addition, the dose constraints assigned to critical structures in the optimization process allow better preservation of organs' function than achieved by the conventional two-dimensional 3DCRT.[11] The purpose of our study was to compare 3DCRT and IMRT with GMB, evaluating and comparing both techniques with regard to target coverage and doses to OARs.


  Materials and Methods Top


Patients

The present retrospective study includes 12 consecutive patients with a histologically proven GBM (Grade IV) treated with an intensity-modulated radiotherapy (IMRT) at our institute. All the patients underwent maximal surgical resection followed by concurrent temozolomide (TMZ) chemotherapy followed by daily along with external beam radiation of 60 Gy in 30 fractions over 6 weeks followed by adjuvant TMZ for 5 days of treatment per month. Ten previously irradiated patients of GMB were retrieved and replanned with 3DCRT techniques. The present study uses four beams for 3DCRT plans with energy 6MV photon [Figure 2], and seven beams for IMRT with Same energy [Figure 3]. A dosimetric comparison was done by performing 3DCRT and IMRT plans for the same patient. Prescription dose and normal tissue constraints were identical for the 3DCRT and IMRT plans.
Figure 1: This CT image shows typical structures encountered in planning a GBM treatment. The structures are GTV, PTV, Organs at risk (OAR) left and right eye, left and right optic nerves, optic chiasm, brain stem, left and right lens

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Figure 2: The dose distribution and beam arrangement in which four non-coplanner beams were used in 3DCRT to cover 95% of target volume with the prescribed dose

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Figure 3: The dose distribution coverage and beam arrangement in which seven non-coplanner beams were used in IMRT to cover 95% of target volume with the prescribed dose

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Treatment simulation, treatment planning volumes, and organs at risk delineation

Target volumes and OARs were delineated on original treatment planning computed tomography (CT) scans on axial views. Patients were immobilized with a thermoplastic mask in a supine position and underwent CT scanning. The CT slices were acquired every 3 mm transferred to the treatment planning system (TPS) and fused with the preoperative magnetic resonance imaging (MRI) studies for gross tumor volume (GTV) delineation. The Radiation Therapy Oncology Group guidelines were used to define target volumes [Figure 3].

  • GTV corresponded to the tumor enhanced by contrast agent (T1 gadolinium sequence) and/or the surgical area
  • Clinical target volume (CTV) corresponded to GTV with a margin to include potential microscopic extensions.


This volume was adapted to the OAR and limited by anatomical boundaries.

  • CTV gadolinium = GTV + 15 mm
  • CTV FLAIR included the volume of MRI T2 FLAIR enhanced with a 5–8 mm margin
  • CTV = CTV FLAIR (MRI T2 FLAIR) + CTV gadolinium
  • PTV corresponded to CTV with a margin to take into account uncertainty in patient's position during treatment. This margin was classically from 3 to 5 mm.


Organs at risk

The OARs including the left and right eye, left and right optic nerves, left and right temporal lobes, brainstem, left and right lens, optic chiasm, left and right cochlea were contoured [Figure 3]. Dose constraints were used for OARs based on the report by Quantitative Analyses of Normal Tissue Effects in Clinic.[13],[14]



An attempt was made to keep the lens doses as low as possible. The acceptable target coverage was defined as the minimum dose ≥95% and maximum dose ≤107% of the prescribed dose.

Treatment planning evaluation

The dosimetric analysis of 3DCRT and IMRT plans was performed for each patient by both qualitative and quantitative measures. The qualitative evaluation is important for location of hot and cold areas in the treatment plans. The quantitative evaluation included the maximum, minimum, mean dose, and dose–volume histogram (DVH). The DVH of both techniques was generated to evaluate the minimum and maximum doses to PTV (Dmin and Dmax, respectively) and OAR Cancel (90). The parameters, D98%, D95%, and D2% were used for plan evaluation, where D98% and D2% values are defined as the dose received by 98% and 2% of the PTV volume, these two values are represented the maximum and minimum doses in the PTV, D95% is target volume covered by 95% of the prescribed dose; for OARs, the mean and maximum doses for brainstem, optic nerve, and lenses were used for treatment plan evaluation. We used DVH analysis for OARs and PTV to evaluate the plans data such as the homogeneity of dose distribution and target dose conformity for the PTV.

Homogeneity index (HI) is a common tool used to analyze dose homogeneity in tumor volume, as shown in equation (1). It is used to compare the dose distributions of many treatment plans.[15]



Where D2% and D98% represent the doses of the PTV, respectively, D98% means that at least 98% of the PTV receives this dose, and hence, D2% means that at least 2% of the PTV receives this dose. D2% is considered to be the maximum dose and D98% is considered to be the minimum dose; lower HI values mean a more homogenous target dose.[16]

The conformity index (CI) is defined as the ratio of volume of tissue receiving at least 95% of the prescribed dose divided by volume of PTV as shown in equation (2). The conformity measures the dose distribution in the target volume. A CI value closer to 1 is more conformal.[17]



Statistical analysis

The data were statistically described in terms of mean ± standard deviation (SD). Analysis was performed by using a paired two-tailed Student's “t”-test. The test was applied to calculate the difference between two means. P ≤ 0.05 was considered statistically significant.


  Results Top


The dose distributions and DVHs of PTV and relevant critical structures from the 3DCRT and IMRT plans were assessed and compared. The benefit of IMRT is more pronounced when the tumors are located in more difficult-to-treat locations, such as the inferior temporal lobe, or brainstem. The dosimetric data were obtained from DVHs generated in the Varian Eclipse TPS. The two different plans were generated in the CT image set of every individual patient, the data are considered matched pair, and paired t-test was applied to calculate the difference between two means. All the dosimetric values are reported in mean ± SD values. All statistical analysis was carried out with 5% level of significance and P < 0.05 was considered statistically significant. The comparison of dose–volume parameters regarding PTV and OARs is shown in [Table 1] and [Table 2].
Table 1: Comparison of dosimetric parameters of planning target volume

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Table 2: Comparison of dosimetric parameters of organ at risk

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Planning target volume dosimetry

The mean, minimum, and maximum PTV dose for IMRT are 60.49 ± 0.74, 62.99 ± 0.67, and 55.87 ± 1.81 and for 3DCRT are 59.83 ± 0.90, 63.96 ± 1.25, and 51.86 ± 2.95 [Figure 1],[Figure 2],[Figure 3]. The P value for mean, minimum, and maximum PTV is 0.14, 0.4, and 0.003, which are statistically significant [Table 1].

The coverage of PTV98%, PTV90%, and PTV5% in IMRT was 57.89 ± 0.94, 58.73 ± 0.69, and 62.59 ± 0.93, respectively, and in 3DCRT was 58.89 ± 0.32, 60.15 ± 1.11, and 61.69 ± 0.69, respectively.

The mean and SD of CI for IMRT is 0.99 ± 0.001 and for 3DCRT is 0.97 ± 0.02, and P = 0.001, which is statistically significant. The HI for IMRT is 1.03 ± 0.02 and for 3DCRT is 1.06 ± 0.009, and P = 0.003 which is statistically significant [Table 1].

Organs at risk dosimetry

The maximum dose of the brainstem for IMRT was 51.84 ± 4.43 and 57.98 ± 4.99 for 3DCRT, and P = 0.09 which is systematically significant. The IMRT plans also provided reduced maximum dose to the optical chiasm (44.61 ± 3.72), left optic nerve (46.08 ± 10.58), right optic nerve (44.63 ± 13.54), left lens (5.45 ± 1.84), and right lens (5.07 ± 0.63) relative to the 3DCRT plans for optical chiasma (49.16 ± 13.00), left optic nerve (44.13 ± 2.74), right optic nerve (49.73 ± 1.82), left lens (7.07 ± 0.81), and right lens (5.84 ± 2.65). The mean doses to the right and left eyes in IMRT were 14.40 ± 4.87 and 18.66 ± 8.92 relative to 3DCRT plans as 19.93 ± 0.83 and 15.84 ± 2.65 [Table 2].


  Discussion Top


The present study favored IMRT in terms of dose of coverage to the PTV and sparing of OAR. Most tumors require radiation therapy due to the biological characteristics of the tumor at the site and limitation of anatomical site. Intensity-modulated radiotherapy (IMRT) allows delivery of a high dose of radiation to a target while sparing surrounding critical structures. It is produced by delivering multiple beamlets of radiation, from many angles incident on a target. These individual beamlets are dynamically shaped so that different areas within the target can receive different doses of radiation simultaneously. It far better achieves the standard goals of radiation therapy: to deliver a high dose of radiation to the target and spare the normal tissues, than conformal RT. As IMRT allows better target coverage and dose conformity with complex, irregular shapes, it is also able to reduce toxicity by achieving a better dose gradient between the target and normal tissues.[4],[5],[6],[7]

The benefits of using IMRT in central nervous system planning are particularly evident in difficult locations such as those close to the brainstem or orbit where it is almost impossible to achieve adequate dose coverage of the target while meeting organ dose constraints of the adjacent critical structure. The use of IMRT allows the production of plans with a variable dose, a graduated dose, or simultaneous integrated boosts. IMRT permits the RT planner to specify dose limits to individual organs, including the hippocampus, potentially decreasing long-term toxicity.

A comparative dosimetric study done by Wagner et al.[9] and Thilmann et al.[3] pointed out that IMRT achieved better target coverage with respect to 3DCRT, scoring a V95% improvement of 13.5 and 13.1%, respectively. This advantage was much more significant when PTV was in proximity of OAR. MacDonald et al.[11] compared the dosimetry of the three-dimensional conformal radiation therapy and intensity-modulated radiation therapy techniques in patients treated for high-grade glioma. The prescription dose and normal tissue constraints were identical for the 3DCRT and IMRT plans. The IMRT significantly increased the tumor control probability (P ≤ 0.005) and lowered the normal-tissue complication probability for brain and brainstem (P < 0.033).

Various studies have mentioned that intensity-modulated radiotherapy (IMRT) is better than the 3DCRT in RT for high-grade glioma.[4],[5],[6],[7] As mentioned in the Introduction section, Lorentini et al.[10] reported that the higher the number of PTV-OARs overlaps, the IMRT provides better target coverage compared with a 3DCRT technique.


  Conclusion Top


The study shows that IMRT treatment achieves better target conformity and better PTV homogeneity and has reduction in maximum dose of selected OARs. IMRT is a superior technique with respect to 3DCRT when there overlaps between OARs and PTV. In these situations, IMRT allows a better target coverage by maintaining OARs sparing. Combination of modern tumor imaging technology with IMRT technique will permit more accurate radiation dose intensification without increasing injury to normal brain and adjacent critical structures. Moreover, in the era of more effective systemic treatments and an increased number of long-term survivors, the use of IMRT may minimize toxicity and improve quality of life.

Ethical approval

For this type of retrospective study, formal consent is not required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.  Back to cited text no. 1
    
2.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.  Back to cited text no. 2
    
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Suzuki M, Nakamatsu K, Kanamori S, Okumra M, Uchiyama T, Akai F, et al. Feasibility study of the simultaneous integrated boost (SIB) method for malignant gliomas using intensity-modulated radiotherapy (IMRT). Jpn J Clin Oncol 2003;33:271-7.  Back to cited text no. 3
    
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Burnet NG, Jena R, Burton KE, Tudor GS, Scaife JE, Harris F, et al. Clinical and practical considerations for the use of intensity-modulated radiotherapy and image guidance in neuro-oncology. Clin Oncol (R Coll Radiol) 2014;26:395-406.  Back to cited text no. 4
    
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Amelio D, Lorentini S, Schwarz M, Amichetti M. Intensity-modulated radiation therapy in newly diagnosed glioblastoma: A systematic review on clinical and technical issues. Radiother Oncol 2010;97:361-9.  Back to cited text no. 5
    
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Hermanto U, Frija EK, Lii MJ, Chang EL, Mahajan A, Woo SY. Intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy for high-grade gliomas: Does IMRT increase the integral dose to normal brain? Int J Radiat Oncol Biol Phys 2007;67:1135-44.  Back to cited text no. 6
    
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Chan MF, Schupak K, Burman C, Chui CS, Ling CC. Comparison of intensity-modulated radiotherapy with three-dimensional conformal radiation therapy planning for glioblastoma multiforme. Med Dosim 2003;28:261-5.  Back to cited text no. 7
    
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Wang M, Ma H, Wang X, Guo Y, Xia X, Xia H, et al. Integration of BOLD-fMRI and DTI into radiation treatment planning for high-grade gliomas located near the primary motor cortexes and corticospinal tracts. Radiat Oncol 2015;10:64.  Back to cited text no. 8
    
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Wagner D, Christiansen H, Wolff H, Vorwerk H. Radiotherapy of malignant gliomas: Comparison of volumetric single arc technique (RapidArc), dynamic intensity-modulated technique and 3D conformal technique. Radiother Oncol 2009;93:593-6.  Back to cited text no. 9
    
10.
Lorentini S, Amelio D, Giri MG, Fellin F, Meliado G, Rizzotti A, et al. IMRT or 3D-CRT in glioblastoma? A dosimetric criterion for patient selection. Technol Cancer Res Treat 2013;12:411-20.  Back to cited text no. 10
    
11.
MacDonald SM, Ahmad S, Kachris S, Vogds BJ, DeRouen M, Gittleman AE, et al. Intensity modulated radiation therapy versus three-dimensional conformal radiation therapy for the treatment of high grade glioma: A dosimetric comparison. J Appl Clin Med Phys 2007;8:47-60.  Back to cited text no. 11
    
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Sakanaka K, Mizowaki T, Hiraoka M. Dosimetric advantage of intensity-modulated radiotherapy for whole ventricles in the treatment of localized intracranial germinoma. Int J Radiat Oncol Biol Phys 2012;82:e273-80.  Back to cited text no. 12
    
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Mayo C, Martel MK, Marks LB, Flickinger J, Nam J, Kirkpatrick J. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys 2010;76:S28-35.  Back to cited text no. 13
    
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Lawrence YR, Li XA, el Naqa I, Hahn CA, Marks LB, Merchant TE, et al. Radiation dose-volume effects in the brain. Int J Radiat Oncol Biol Phys 2010;76:S20-7.  Back to cited text no. 14
    
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Feuvret L, Noël G, Mazeron JJ, Bey P. Conformity index: A review. Int J Radiat Oncol Biol Phys 2006;64:333-42.  Back to cited text no. 15
    
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Yoon M, Park SY, Shin D, Lee SB, Pyo HR, Kim DY, et al. A new homogeneity index based on statistical analysis of the dose-volume histogram. J Appl Clin Med Phys 2007;8:9-17.  Back to cited text no. 16
    
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Foroudi F, Wilson L, Bressel M, Haworth A, Hornby C, Pham D, et al. A dosimetric comparison of 3D conformal vs. intensity modulated vs. volumetric arc radiation therapy for muscle invasive bladder cancer. Radiat Oncol 2012;7:111.  Back to cited text no. 17
    


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