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Year : 2014  |  Volume : 10  |  Issue : 1  |  Page : 56-61

Implementation of a wedged-dynamic arc therapy technique for head and neck cancer

1 Department of Radiation Physics, Oncology and Hematology Hospital, Maadi Armed Forces Medical Compound, Cairo, Egypt
2 Department of Radiotherapy Physics, Beatson West of Scotland Cancer Centre, United Kingdom
3 Department of Physics, Faculty of Science, Ain Shams University, Cairo, Egypt

Date of Web Publication23-Apr-2014

Correspondence Address:
Mohamed S Ibrahim
Radiotherapy Physicist, Department of Radiation Physics, Oncology and Hematology Hospital, Maadi Armed Forces Medical Compound, Cairo
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Source of Support: The work was primarily carried out at Radiation Physics Department, Oncology and Hematology Hospital, Maadi Armed Forces Medical Compound, Cairo, Egypt, Authors, Conflict of Interest: None

DOI: 10.4103/0973-1482.131369

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 > Abstract 

Introduction: In this study, we designed and evaluated a wedged dynamic arc therapy (W-DAT) to provide the desirable concaved-shape dose distribution to cover the target in the treatment of head and neck sequence cell carcinoma.
Materials and Methods: Eight patients were treated using W-DAT. The dose prescriptions were 70 Gy and 54 Gy, in 35 fractions, to the sites of the gross planning target volume (PTV1) and the microscopic (PTV2) diseases respectively. This technique consists of four wedged half-arcs of moving multi-leaf collimator leaves to fit PTV1 and shield brain stem at all gantry rotations. These were combined with two anterior-posterior conformal fields of different weighing to improve the dose uniformity. Another two anterior-posterior conformal fields were designed to cover the PTV2. All of the eight fields were half blocked by the normal jaws so there is no dose overlap at the interface between the two targets.
Results: Referring to radiation therapy oncology group protocol 0615, 95% of the PTV1 was covered by more than 95% (66.50 Gy) of the prescribed dose, with very low dose inhomogeneity index of 0.0670 ± 0.0007. The maximum dose to 1% of the planning organ at risk volumes-brainstem didn't exceed 56.10 ± 2.17 Gy while the two parotids were well spared as they received a mean dose of 21.97 ± 3.24 Gy. Isocentric ion chamber measurements showed good agreement with the treatment planning system calculated dose with the maximum deviation of 2.40% while film measurements yielded lesser than 4.20% of the pixels failed the acceptance gamma criteria of (3 mm, 3%).
Conclusion: W-DAT technique was approved in our department as the standard choice for the radical treatment of head and neck sequence cell carcinoma.

 > Abstract in Chinese 

结果:参照肿瘤放射治疗学组研究方案0615,PTV1的95%被覆盖是通过实际超过95%(66.50Gy)处方剂量,不均一性指数非常低0.0670± 0.0007。脑干1%容量最大剂量不超过56.10± 2.17Gy,两侧腮腺也被保护,平均剂量21.97± 3.24Gy。中心离子室测量证实该系统的良好相符性,仅2.4%的最大偏差,而薄膜测量稍差,少于4.2%像素,不符合γ-标准的(3mm, 3%)。

Keywords: Dynamic arc, head and neck sequence cell carcinoma, intensity modulation, radiation dosimetry

How to cite this article:
Ibrahim MS, Metwaly M, El-Sayed ESM, Sallam ASM. Implementation of a wedged-dynamic arc therapy technique for head and neck cancer. J Can Res Ther 2014;10:56-61

How to cite this URL:
Ibrahim MS, Metwaly M, El-Sayed ESM, Sallam ASM. Implementation of a wedged-dynamic arc therapy technique for head and neck cancer. J Can Res Ther [serial online] 2014 [cited 2019 Sep 15];10:56-61. Available from: http://www.cancerjournal.net/text.asp?2014/10/1/56/131369

 > Introduction Top

Radiotherapy is a primary treatment modality for head and neck sequence cell carcinoma and local control of the disease is directly related to the radiation dose delivered to the target volume. [1],[2] With conventional external beam techniques, however, dose escalation is hindered by the tolerance of critical normal tissues in close proximity to the target volume. For example, both parotid glands are often included in the high-dose region and xerostomia is thus inevitable, causing discomfort and the development of dental caries. [1],[3] Three-dimensional conformal radiotherapy (3D-CRT), consisting of computed tomography (CT)-assisted 3D-planning techniques and multiple-shaped fields can concomitantly improve tumor coverage in this site and decrease normal tissue doses. [4] Intensity-modulation radiation therapy (IMRT), with its ability to produce high-dose gradients between the target volume and the organs at risk (OAR), has become a favorable option for head and neck treatment. However, because it is based on inverse planning calculation algorithm, the IMRT demands pre-treatment dose validation to assure safe treatments. This increased treatment efforts compared with conventional radiotherapy and 3D-CRT. Besides the dynamic/static multi-leaf collimator (MLC) modulation in IMRT requires increased treatment times (monitor units [MUs]). As the multiple static IMRT beams are not sufficiently adequate to deliver dose to the tumor as well as sparing healthy organs, an additional option of rotating the gantry were added recently. This technique is called volumetric-modulated arc therapy (VMAT). Further improvement of the treatments efficiency have been added with VMAT. [5],[6] however, the complexity of its inverse planning algorithm has made the pre-treatment quality assurance more essential.

In fact, the current study is an application of what is called dynamic arc therapy (DAT) in the head and neck treatments. DAT is basically, an additional option of rotating gantry while the MLC is shaping the tumor and shielding some OAR. This technique had been published and applied successfully for the treatment of prostate cancer. [7],[8] When a static wedge is attached to the rotating gantry the technique is known as wedged dynamic arc therapy (W-DAT). Consequently, one can consider this technique as one step forward of the 3D-CRT toward to provide the complex concave dose distribution. This mean that the pre-treatment quality assurance is less essential in comparison of the inverse planning techniques and can be phased out with more reliance on the visual inspection of the MLC movement with the beam eye view in the planning system and with the periodic dynamic MLC quality assurance.

 > Materials and Methods Top

Patient and staging evaluation

Eight patients with head and neck sequence cell carcinoma (nasopharynx and oropharynx) were treated using W-DAT technique. The cancer had any tumor size, negative lymph nodes and no metastasis so this technique was implemented with cases that have (T Any N 0 M 0 ) stages.

CT and volume definition

All patients were immobilized in the supine position with head and neck thermoplastic mask. We preformed CT with slice spacing of 1.25 mm for eight patients of interest. The scan limits were taken through the region from the vertex to 5-cm inferior to the clavicular heads. The CT images were transferred electronically to our Eclipse 3D planning system (version 8.6: Varian Medical Systems, Palo Alto, CA). Varian 23 EX linear accelerator with an 80-leaf (40-pair) MLC, 1 cm width at the isocenter, was used with 6 MV photon beam for treatment delivery.

The clinical target volume (CTV) was defined as the gross target volume (GTV) plus a margin of 5 mm in all directions including the entire nasopharynx, retropharyngeal nodes, clivus, skull base, inferior sphenoid sinus, pterygoid fossae, parapharyngeal space and posterior nasal cavity. [9] The GTV, CTV and OAR were delineated on a series of treatment planning CT images. For nasopharyngeal carcinoma cases, the neck nodes were frequently involved. Because of the drastic anatomic differences, treatment of the primary tumor was separated from treatment of the neck nodes. The radiation therapy oncology group (RTOG protocol 0615) was selected as the main guide line for all volume definitions and planning evaluation. The planning target volume (PTV) was defined as the CTV plus a margin of 5 mm in all directions. PTV was divided into two parts: First primary tumor only (PTV1), the second upper and lower neck (PTV2). A virtual brain stem volume was delineated away from PTV1 by 7 mm and this volume was defined only for planning purpose, with no role in plan evaluation. It was shielded by the dynamic arc techniques to minimize the effect of the MLC penumbra on the PTV1 coverage. Two more volumes of 1 mm margin to each of the brain stem and spinal cord were delineated as planning organ at risk volumes (PRVs), according to RTOG protocol 0615. The volumes were used for evaluation purpose and are designated as PRV-brain stem and PRV-spinal cord. Moreover, the parotids were considered as crucial organs to be saved in order to reduce the potential of irreversible and permanent xerostomia. [10]

Dose prescription

For W-DAT plans, the gross tumor (PTV1) will receive 35 fractions of 2 Gy/fraction, total 70 Gy. And neck nodes (PTV2) will receive 35 fractions of 1.54 Gy/fraction, total 54 Gy. The treatment will be delivered once daily, 5 fractions per week, over 7 weeks. All targets had been treated simultaneously. [10],[11]

W-DAT technique

In the analogy of the previously applied technique for prostate, [8] four half arcs covering 350° (0°-165°, 165°-0°, 185°-0°, 0°-185°) with a hard 45° wedge was applied. Each bilateral pair of arcs was in opposite orientations as shown in [Figure 1]. The wedge was inserted at zero angles for both gantry and collimator, such that its thin end was at the left side for left arcs and at the right side for right arcs. All arcs were generated automatically by the planning system to fit the PTV1 and shield the virtual brainstem volume (VBV) by means of MLCs. Two anterior-posterior conformal fields were added conforming the beam's eye view of PTV1 in order to adjust the dose homogeneity to PTV1 while the parotids were shielded. To cover the PTV2 with the prescribed dose, two more anterior-posterior conformal fields were added such that the MLCs fit the PTV2 and shielded the spinal cord. All eight fields were half-beam blocked to the central axis so as to avoid dose overlapping, as shown in [Figure 2].
Figure 1: Fields arrangement and isodose distribution for wedged dynamic arc therapy technique in transversal, frontal, sagittal and the dose-volume histograms for planning target volume (PTV1), PTV2 and organs at risk

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Figure 2: (a) The two anterior-posterior conformal fields conforming to the beam's eye view of planning target volume (PTV1) (b) Another two anterior-posterior conformal fields conforming to the beam's eye view of PTV2

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Plan evaluation and comparisons

The dose-volume histograms (DVHs) for all PTV1s and OAR were used for plan evaluation and comparisons. All plans were normalized based on the DVHs to ensure that 95% of the PTV1 received 100% of the prescribed dose. The dose inhomogeneity (DI) in the PTV1 was defined as (D 5% − D 95% )/D mean , [12] where D 5% and D 95% are the doses to the 5% and 95% of the PTV1 respectively while D mean is its mean dose value.

The W-DAT plans were considered acceptable if they satisfied the dose guidelines designed by the RTOG protocol 0615 for patients being treated for head and neck sequence cell carcinoma. [10]

Plan verification

Ion chamber and film measurements were performed to verify the doses calculated by the Eclipse planning system for the W-DAT plans. The plans for all patients were exported in Eclipse to the CT images of a cylindrical phantom (PTW T9193: PTW, Freiburg, Germany) and test plans were calculated for comparison with ion chamber measurements. On the other hand, the patients' plans were exported to the CT images of an Alderson Rando anthropomorphic phantom (PTW) and another set of test plans were prepared for film measurements.

Before the delivery of the test plans, the routine machine output measurement was performed for the 6 MV photon beam so as to create the dosimetric base line for both ion chamber and film measurements. Film calibration was performed with five kodak extended dose range (EDR2) films (Gammex rmi, Middleton, WI) and 30 cm Χ cm 30 Χ 30 cm solid water phantom (PTW-29672: PTW) typically as previously published. [7],[8] For each plan a pinpoint ion chamber (PTW 31006, 0.015 cm 3 : PTW) located at the central axis of the cylindrical phantom was used to verify the isocenter point dose, while an EDR2 film was inserted axially into the Alderson phantom at the region of the primary tumor to carry out the 2D dose measurement. The measured and calculated dose planes were imported and compared using Varisoft software (version 3.1: PTW). The criterion used to evaluate the accuracy of the Eclipse calculations was the gamma index with individual acceptance criteria of 3% dose difference (DD) and 3 mm distance to agreement (DTA). [13] A quantitative analysis of the dose distribution comparison, based on gamma reports, was performed to show the percentage pixels in the scanned area that exceeded the acceptance criteria (percentage failed pixels).

 > Results Top

W-DAT plan evaluation

Since our selected guideline was the RTOG protocol 0615, all the related dose statistics were obtained from the DVH's of the target volumes and the various OAR, as illustrated in [Table 1]. In terms of the dose coverage to the primary target volume PTV1, the obtained results indicate that 95% of the volume was covered by more than 95% (D 95% >66.50 Gy) of the prescribed dose while the maximum dose (D max ) in the target didn't exceed 107.6% with no tissue outside it receiving more than 110%. The homogeneity of PTV1 dose distribution was pretty good as indicated by estimated small DI value of 0.067 ΁ 0.0007, which reflects a satisfactory degree of similarity between the doses that covers 95% and 5% of the volume. On the other hand, the dose statistics of the secondary target volume PTV2 shows that the W-DAT technique achieved the intended dose coverage, as D mean and D 50% equated 104.80% and 103.00% of the prescribed dose of 54 Gy respectively. As is normally expected with the two parallel opposing ports, the D max was fairly high (115.87%), but didn't cover that much of the target (5.00%) and consequently the dose distribution was reasonably acceptable form clinical point of view.
Table 1: The dose statistics extracted from the DVH's of the different volumes/organs of interest with the W - DAT technique

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Since the ultimate objective of the W-DAT was to create the concaved-shape dose distribution in order to protect the brain stem as shown in [Figure 1], it was the first OAR interested us. The brain stem D max (57.10 ΁ 2.20 Gy) was found to be 5.56% higher than the minimum acceptable dose level of (54 Gy) according to the RTOG protocol 0615. This prompted us to find out the dose to 1% of the PRV-brain stem (D 1%) which was found 6.48% lower than acceptable dose level of (60 Gy). The reason for the relative high doses to the brain stem was that some of our cases were having tumor extensions to the bony structure surrounding, it which enforced the MLC to provide the minimum requirement of protection only. In contrast, the D max of the spinal cord and D 1% of the PRV-spinal cord were well below the acceptable of 45 Gy and 50 Gy respectively, as the organ is located in the low dose prescription region.

Since the W-DAT technique is composed of a symmetric beam arrangement, the parotids in both sides received almost the same amounts of doses, as shown in [Table 1]. Neither the D mean doses nor the doses to 20 cc (D 20cc ) of each parotid exceeded the mentioned dose constrains of 26 Gy and 20 Gy in the RTOG protocol 0615 respectively. This was also the case for the mandible dose as it satisfied easily the recommended dose sparing condition of a < 70 Gy D max as well as no more than 1cc of its volume had a dose exceeded 75 Gy (D 1cc < 75 Gy).

Furthermore, all delivered doses to the optical organs were quite below the critical dose levels as they were all located in the superior penumbrae of the radiation fields. For example, the maximum received a dose by the optic chiasm was as much as one-third of the permissible dose value (50 Gy).

W-DAT plan verification

The ion chamber measurements, which were performed at the isocenter of the cylindrical phantom, indicated that the measured doses agree with those calculated at the same point. [Figure 3] shows the percentage variation of the calculated and measured doses at the level of the primary tumor (PTV1) and brain stem for all patients. The maximum deviation between the measured and calculated doses at the primary tumor level was 2.40% while the maximum deviation between the measured and calculated doses at the brain stem region was 3.70%. [Figure 4] presents an example of gamma index distributions of the measured and calculated dose distributions in the primary tumor level. The main region of dose distribution that failed the acceptance criteria (3% DD and 3 mm DTA) was located in the low-dose regions. The percentage of failed pixels in the dose distribution at the primary tumor and at the junction levels didn't exceed 4.3% and 6.6 with any patient respectively.
Figure 3: Deviation between the measured and calculated dose for (a) primary tumor level and (b) brain stem level

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Figure 4: Example of gamma index distributions for the measured and calculated dose distributions for the primary tumor level

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 > Discussion Top

W-DAT technique was implemented with eight cases that have (T Any N 0 M 0 ) stages where the intended concave dose distribution to deliver 70 Gy to the primary tumor with the necessary protection to the OAR. This technique proved many advantages such as high homogeneity curable doses to the target with sparing of the brain stem and preserving the salivary function by reducing doses to parotid glands. To find out the status of the W-DAT technique in the latest DAT modalities of head and neck cancer, three of the recently published data [5],[6],[14] have been selected for comparison purposes. In this discussion, we will be focusing on the high dose region (PTV1), where the W-DAT is applied. Volumes such as PTV2, spinal cord, optic nerves and optic chiasm, which are located in the low dose region, will not be considered in the following investigations.

The first published technique of interest was IMRT with the prescribed dose of 70 Gy to the primary tumor sites (PTV1) and 54 Gy to the neck nodes (PTV2). [14] It was found that there is no perceptible difference in PTV1 doses between the W-DAT and IMRT techniques, since the mean and D max of the PTV1 with W-DAT increased only by 0.28% and 1.07% respectively. On the other hand, the doses to the parotids in the present study were reduced by as much as 10%. This reduction was due to the proper shielding of parotid by means of MLCs with the anterior-posterior conformal fields of the W-DAT technique in PTV1 region. However, a slight difference in the D 1% of the PRV-brain stem was noted with the current technique, since it was 6.4% higher than that it was with the IMRT technique.

The second closely related and recently published study included a comparison of the three techniques IMRT, volumetric modulated arc therapy with the SmatArc of Elekta linac (VMAT-S) and helical tomotherapy (HT). [5] In that publication, plans for eight patients were computed for both IMRT and VMAT-S along with HT. The dose prescriptions were 70 Gy and 58.10 Gy to regions of macroscopic and microscopic low-risk disease (PTV1 and PTV2 in the current study) respectively. Compared with the W-DAT the mean dose to the PTV1 was slightly high, by 0.20%, 0.30% and 0.30% compared with IMRT, VMAT-S and HT respectively. Also, the D 1% of the PRV-brain stem with W-DAT was noticeably higher, 26.00%, 26.60% and 26.30% compared with IMRT, VMAT-S and HT respectively. However, great sparing of the ipsilateral and contralateral parotid glands was achieved in the present study, as they were (38.80% and 28.50%), (38.20% and 25.40%) and (36.10% and 25.40%) lower than those with IMRT, VMAT-S and HT techniques respectively. Besides, the D 1cc of mandible with W-DAT was markedly lower, by 9.40%, 8.40% and 11.50% compared with IMRT, VMAT-S and HT respectively. This was due to the reasonable cut-off of high-dose isodose lines surrounding the PTV1 observed with the W-DAT as shown in the transverse plan in [Figure 1]. Regarding the efficiency of the treatment delivery, [Table 2] shows the estimated the beam delivery times and the number of delivered MUs with W-DAT in comparison with IMRT and VMAT-S. It was noticed that W-DAT offers shorter delivery times of about half and one-third comparing with VMAT-S and IMRT respectively. The longer deliver time with VMAT-S can be attributed to the fact that the range of MLC leaf positions variation was restricted to 2 cm per gantry angle increment of 4°. This resulted in possible delay of the leave motion across the target or a possible delay in gantry speed to optimize dose shaping. [5] In contrast, with W-DAT the gantry was always moving with its maximum speed (64 s/350°) regardless the MLC leaf positions with a dose rate variation to preserve MLC leaf movement within its speed limits. IMRT was a nine-field delivered in step and-shoot technique with approximately 12-15 segments per beam. This technique resulted longer treatment time due to the longer beam hold time between the consecutive segments of every field. So that number of MU per fraction with the W-DAT and VMAT-S techniques were about 20% and 28% less than that with the IMRT respectively.
Table 2: Delivery parameters by technique

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In the third technique, [6] the same PTV1 dose (70 Gy) was delivered with two complementary coplanar arcs of 358°. A sequential approach was used, in which the first arc plan was used as a base dose plan for the second arc plan, which compensated for possible under or over dosage in the first arc plan, leading to a homogeneous dose in the PTV1. [6] There is no adequate difference of PTV1 dose between the present study W-DAT technique and Rapidarc technique since the minimum dose to PTV1 in W-DAT technique decreased by 1.10% and the D max to PTV1 in W-DAT technique increased by 2.60%. In the present study, an adequate sparing of parotid glands, since the doses to it were reduced by 34.70% and 21.10% by comparing with ipsilateral and contralateral parotid glands in Rapidarc technique respectively. The D max to the spinal cord was reduced by 52% comparing with Rapidarc technique. Slight reduction in the D max of the brain stem by 2% is in favor of the present technique. Moreover, delivery of Rapidarc plans is possible in <3 min while W-DAT technique needed about 5 min. [6]

 > Conclusions Top

to the RTOG protocol 0615, the single-phase W-DAT technique have produced the favorable concave dose distribution to achieve the desirable dose coverage to the primary target and acceptable dose protection to the OAR with eight selected cases of head and neck sequence cell carcinoma. Pre-treatment quality assurance with both of the ion camber and film measurements proved its safety and consequently, the technique has been routinely implemented.

 > References Top

1.Kutcher GJ, Fuks Z, Brenner H, Brown AP, Burman C, Cheng E, et al. Three-dimensional photon treatment planning for carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys 1991;21:169-82.  Back to cited text no. 1
2.LoSasso T, Chui CS, Kutcher GJ, Leibel SA, Fuks Z, Ling CC. The use of a multi-leaf collimator for conformal radiotherapy of carcinomas of the prostate and nasopharynx. Int J Radiat Oncol Biol Phys 1993;25:161-70.  Back to cited text no. 2
3.Xia P, Fu KK, Wong GW, Akazawa C, Verhey LJ. Comparsion of treatment plans involving intensity modulated radiotherapy for nasopharyngal carcinoma. Int J Radiat Oncol Biol Phys 2000;48:329-37.  Back to cited text no. 3
4.Leibel SA, Kutcher GJ, Harrison LB, Fass DE, Burman CM, Hunt MA, et al. Improved dose distributions for 3D conformal boost treatments in carcinoma of the nasopharynx. Int J Radiat Oncol Biol Phys 1991;20:823-33.  Back to cited text no. 4
5.Clemente S, Wu B, Sanguineti G, Fusco V, Ricchetti F, Wong J, et al. Smartarc-based volumetric modulated arc therapy for oropharynegal cancer: A dosimetric comparison with both intensity-modulated radiation therapy and helical tomotherapy. Int J Radiat Oncol Biol Phys 2011;80:1248-55.  Back to cited text no. 5
6.Doornaert P, Verbakel WF, Bieker M, Slotman BJ, Senan S. Rapid arc planning and delivery in patients with locally advanced head and neck cancer undergoing chemotherapy. Int J Radiat Oncol Biol Phys 2011;79:429-35.  Back to cited text no. 6
7.Metwaly M, Awaad AM, El-Sayed el-SM, Sallam AS. Forward-planning intensity-modulated radiotherapy technique for prostate cancer. J Appl Clin Med Phys 2007;8:2488.  Back to cited text no. 7
8.Metwaly M, Awaad AM, El-Sayed el-SM, Sallam AS. Comparison of intensity-modulated radiotherapy and forward-planning dynamic arc therapy techniques for prostate cancer. J Appl Clin Med Phys 2008;9:2783.  Back to cited text no. 8
9.Sultanem K, Shu HK, Xia P, Akazawa C, Quivey JM, Verhey LJ, et al. Three-dimensional intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: The university of California-san Francisco experience. Int J Radiat Oncol Biol Phys 2000;48:711-22.  Back to cited text no. 9
10.A Phase II Study of Concurrent Chemoradiotherapy Using Three-Dimensional Conformal Radiotherapy (3D-CRT) or Intensity-Modulated Radiation Therapy (IMRT)+Bevacizumab (BV) for Locally or Regionally Advanced Nasopharyngeal Cancer, [Current Version Date 2011 Feb 16]. Available from: http://www.rtog.org/ClinicalTrials/ProtocolTable/StudyDetails.aspx?study=0615.  Back to cited text no. 10
11.Hunt MA, Jackson A, Narayana A, Lee N. Geometric factors influencing dosimetric sparing of the parotid glands using IMRT. Int J Radiat Oncol Biol Phys 2006;66:296-304.  Back to cited text no. 11
12.Mock U, Georg D, Bogner J, Auberger T, Pötter R. Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys 2004;58:147-54.  Back to cited text no. 12
13.Low DA, Harms WB, Mutic S, Purdy JA. A technique for the quantitative evaluation of dose distributions. Med Phys 1998;25:656-61.  Back to cited text no. 13
14.Seung S, Bae J, Solhjem M, Bader S, Gannett D, Hansen EK, et al. Intensity modulated radiotherapy for head and neck cancer in community setting. Int J Radiat Oncol Biol Phys 2008;72:1075-81.  Back to cited text no. 14


  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2]


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