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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 5  |  Page : 1005-1010

Dual partial arc volumetric-modulated arc therapy: The game changer for accelerated hypofractionated whole-breast radiotherapy with simultaneous integrated tumor cavity boost in early breast cancer - A comparative dosimetric study with single partial arc volumetric-modulated arc therapy


1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Oncology, Max Institute of Cancer Care, New Delhi, India
3 Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
4 Division of Epidemiology and Biostatistics, ICMR - National Institute of Epidemiology, Chennai, Tamil Nadu, India
5 Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
6 Department of Pulmonary Medicine, All India Institute of Medical Sciences, New Delhi, India
7 Department of Radiation Oncology, National Cancer Institute, All India Institute of Medical Sciences, New Delhi, India

Date of Web Publication4-Oct-2019

Correspondence Address:
Dodul Mondal
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_922_17

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 > Abstract 


Introduction: In a previous study, we demonstrated clinical and dosimetric feasibility of single partial arc volumetric modulated arc therapy (VMAT) for accelerated hypofractionated whole breast radiotherapy with simultaneous integrated boost (SIB) to lumpectomy cavity for early breast cancer. In this dosimetric study, we compared dual partial arcs versus single arc.
Patients and Methods: Fifteen consecutive patients for treatment with hypofractionated accelerated radiotherapy with SIB using VMAT were planned with single partial arc in an earlier study, initial result of which is published elsewhere. The comparative dosimetric plan was created using two partial arcs. Skewness and kurtosis test, Paired Student's t-test, and Wilcoxon signed-rank test were applied for statistical analysis. P < 0.05 was considered statistically significant.
Results: Most planning targets are better achieved with dual arc technique. Coverage of planning target volume (PTV) whole breast (PTVWB) and PTV lumpectomy cavity (PTVBOOST) was significantly improved with dual partial arc without significant difference in conformity index and homogeneity index. Dual arc improved dosimetric parameter significantly. Mean dose (Dmean) and maximum dose (Dmax) of whole breast PTV as well as Dmax of PTVBOOST; ipsilateral and contralateral lung Dmean, Dmax, 5 Gy volume (V5); contralateral lung Dmean, Dmax, V5; Heart V25 and V18; Dmean of 5 mm thickness skin; Dmean and Dmax of ribs; and Dmean and Dmax of contralateral breast were improved with dual arc.
Conclusion: This is first of its kind study establishing the advantage of dual partial arcs in the current context. Dual partial arcs improved dosimetry over single partial arc. Significant dose reduction can be achieved for multiple crucial organs at risk.

Keywords: Accelerated hypofractionation, dual arc, early breast cancer, simultaneous integrated boost, volumetric-modulated arc therapy


How to cite this article:
Mondal D, Julka PK, Sharma DN, Laviraj MA, Jana M, Kamal VK, Deo SV, Guleria R, Rath GK. Dual partial arc volumetric-modulated arc therapy: The game changer for accelerated hypofractionated whole-breast radiotherapy with simultaneous integrated tumor cavity boost in early breast cancer - A comparative dosimetric study with single partial arc volumetric-modulated arc therapy. J Can Res Ther 2019;15:1005-10

How to cite this URL:
Mondal D, Julka PK, Sharma DN, Laviraj MA, Jana M, Kamal VK, Deo SV, Guleria R, Rath GK. Dual partial arc volumetric-modulated arc therapy: The game changer for accelerated hypofractionated whole-breast radiotherapy with simultaneous integrated tumor cavity boost in early breast cancer - A comparative dosimetric study with single partial arc volumetric-modulated arc therapy. J Can Res Ther [serial online] 2019 [cited 2019 Nov 22];15:1005-10. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/1005/244486




 > Introduction Top


Whole breast radiation after breast-conserving surgery for early breast cancer is the standard of care.[1] Standard adjuvant whole breast radiation involves delivering 45–50 Gy in 1.8–2 Gy per fraction over 5 weeks with or without additional boos to tumor cavity. The entire treatment takes 5–6.5 weeks. Multiple randomized studies have proven equivocal or better outcome with hypofractionated radiation or extreme hypofractionation after breast conservation surgery and is being practiced by many centers worldwide.[2],[3],[4],[5],[6]

In a previous study, we have described the background and rationale for a phase I/II study of accelerated hypofractionated adjuvant whole breast radiation with simultaneous integrated boost using volumetric modulated arc therapy (VMAT) for early breast cancer.[7] In this initial study, radiation treatment plans were generated using a single partial arc volumetric modulated arc therapy (VMAT). In this current dosimetric study, we wanted to see whether the addition of a partial arc in the opposite direction to the original partial arc can improve the dosimetry in terms of target coverage and organ sparing compared to single partial arc VMAT.


 > Patients and Methods Top


The details of patients selection criteria, target delineation, and planning details are described elsewhere.[7] Fifteen consecutive patients meeting inclusion and exclusion criteria were planned for the initial study using single partial arc. Fifteen comparative plans were also made for this dosimetric study using two partial arcs. The initial report included first ten patients. This current dosimetric study includes unpublished data from the original study.

Simulation and target delineation

All patients were simulated in the supine position with rigid thermoplastic immobilization device keeping both arms above the head. Planning axial computed tomography (CT) scans were obtained from chin to mid abdomen in large bore CT simulator (Philips Health Care, USA) with 3 mm slice thickness, free breathing and using intravenous iodinated contrast agent. Images were reconstructed, and dataset was transferred to treatment planning system (Monaco Version 5.11.01, Elekta, AB, Stockholm) using Mosaiq Digital imaging and communication in Medicine.

Two different clinical target volumes (CTV) were created. Whole breast CTV (CTVWB) is the entire breast parenchyma as seen in planning CT scan. Boost CTV (CTVBOOST) is the surgical bed, defined by surgical clips placed in the lumpectomy cavity during surgery or seroma, with additional margin of 1.5 cm, edited off from muscle, ribs, lung parenchyma, air, and other structures felt uninvolved by the microscopic tumor extension. 5 mm expansion was given all around the CTVs to generate two separate planning target volumes (PTVs): whole breast PTV (PTVWB) and boost PTV (PTVBOOST); PTV was shaved off skin by 5 mm. No other modification of PTV was allowed as per institutional protocol. Target delineation was done with the help of a radiologist experienced in breast oncology and radiotherapy planning procedures. Normal organs were delineated following RTOG thoracic organ at risk (OAR) contouring guidelines “ Atlas More Detailses for OARs in thoracic radiation therapy.[8]

Dose prescription

40.5 Gy to PTVWB and 48 Gy to PTVBOOST were prescribed in 15 fractions over 3 weeks, with simultaneous integrated boost technique. Criteria for target coverage were: D98% for both PTVWB and PTVBOOST was >95% and D2% for PTVBOOST was <107%. Conformity index was defined as percentage volume of PTV receiving prescribed dose. Homogeneity index was defined as the ratio of dose to 2% and 98% of PTV, respectively. OAR dose constraints are shown in [Table 1].
Table 1: Dose constrains for normal organs at risk

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Planning

VMAT plans are created using 6 MV photon beams commissioned for Elekta Synergy ®-S equipped with beam modulator. This has 40 pairs of interdigitated multileaf collimators with a leaf thickness of 4 mm at isocenter and maximum leaf speed of 2.5 cm/sec. The gantry can move at a maximum speed of 6 cm/s delivering a variable dose rate with a maximum rate of 600 MU/min.

Plans are generated using Elekta Monaco Treatment planning system version 5.11.01 (Elekta Instrument, AB, Stockholm) with dual dose prescription for SIB. Dosimetry with dual partial arc was created by gantry rotation in anticlockwise and clockwise fashion. Arc range is determined according to the width and concavity of the PTV. Entry points for beam were determined from the concept of classical tangent beam planning.

All efforts were made to avoid beam entry to opposite breast and lung. The isocenter was placed at the center of the PTV. Collimator angle was set 90° or 0° depending on the craniocaudal length of the target volume.

Dose calculation and optimization were performed using Monte Carlo photon algorithm with dose grid size of 3 mm and 30° increment. Surface margin (inner margin from skin surface excluded from optimization was set to 0.5 cm, minimum segment width 0.5 cm, 2 cm flash margin to avoid underdosing the skin due to breathing) and maximum number of control points of 180 per plan are used for dose calculation. We used medium fluence for optimization. Dose constraints to the OAR were achieved without compromising PTV coverage.

Statistical analysis

Normally and non-normally distributed continuous variables were presented in mean ± standard deviation and median (p25, p75, or interquartile range), respectively. For checking normality of data, skewness and kurtosis test was applied. Paired t-test was used when continuous variables followed normal distributions, to compare means between two dependent groups; if continuous variables did not follow normal distributions, Wilcoxon signed-rank test to compare medians between two independent groups was utilized. P < 0.05 were taken as significant. Data analysis was done using Stata 12.1 (STATA Corp LLC, USA).


 > Results Top


Almost all dosimetric criteria could be moderately or well achieved with both these techniques. We have already shown good to excellent achievement of dosimetric targets in our previous report using single partial arc. There is no significant difference in conformity index, homogeneity index, or total monitor units (MU) using two partial arcs. Conformity index (CI) for PTVWB was 0.97 with both techniques. CI for PTVBOOST was 0.97 and 0.98 respectively with single and dual arcs. Average HI index was not different between two different techniques. Although average MU was reduced with dual arcs (1100.82 vs. 1076.65), that was not statistically significant.

Average Dmean to PTVWB was significantly reduced by dual arcs (41.7 vs. 42.68 Gy, P = 0.001). There was significant reduction in Dmax of PTVWB (50.25 vs 51.38, P = 0.025) and Dmax of PTVBOOST (52.31 vs. 53.03, P = 0.007) with dual arc technique. D98 improved significantly with dual arc for both PTVWB and PTVBOOST (P = 0.009 and 0.004, respectively). D2cc improved for PTVWB (116.17 vs. 120.93, P < 0.001) but not for PTVBOOST. There was no difference in V107 for both the PTV.

Mean dose, maximum dose, V20, and V5 for ipsilateral lung were significantly reduced using dual arc techniques. Mean dose reduced from 12.6 to 9.3 Gy (P = 0.005), maximum dose reduced from 46.8 to 40.5 Gy (P ≤ 0.001), V20 reduced from 18.80 to 14.47 Gy (P = 0.001) and V5 reduced from 53.8% to 39.6% (P = 0.002). Mean dose, maximum dose, and V5 of contralateral lung were also reduced significantly.

Dual arcs also reduced mean heart dose significantly from 4.56 to 2.81 Gy (P ≤ 0.001). V25 and V18 for heart were also reduced (P = 0.026 and 0.001, respectively).

Maximum dose to ribs was reduced with dual arcs (46.67 vs. 51.47 Gy, P = 0.201) but this was not significant; reduction in mean dose was significant with dual arcs (17.41 vs. 19.23, P = 0.001). Mean and maximum dose to contralateral breast was also reduced significantly with dual arcs (p=<0.001 for both). When skin dose was compared, 5 mm thick skin showed a significant reduction in mean dose (30.6 Gy vs. 31.5 Gy, P = 0.031). [Table 2] shows details of dosimetric results for both techniques.
Table 2: Dosimetric outcome and comparison between two arms

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 > Discussion Top


Accelerated hypofractionation with SIB using VMAT is not commonly practiced. Most centers practice whole breast radiation followed by a sequential boost to lumpectomy cavity even when hypofractionation scheme is used. However, we believed that incorporating SIB could significantly reduce overall treatment time without compromising outcome to treatment and help in treating more patients at the same time. The biologically effective dose of such dose fractionation used in this study reached almost 90 Gy (α/β =4), which can achieve 90% tumor control probability.[9] With single arc, we achieved dosimetric targets decently. We felt that using another partial arc from opposite direction of the first arc might improve the dosimetry. As a result, there were significant gains in few parameters which are known to be clinically relevant.

The overall dosimetry improved significantly using two partial arcs. PTV coverage, Dmean, Dmax and D98 for whole breast PTV improved significantly. D2cc, representing high-dose volume was also reduced significantly. Dmax and D98 to lumpectomy volume were also improved. Target coverage was eventually improved in almost all the parameters. All these improvements made the dose distribution much more homogeneous. Among these achievements, reduction in D2cc of whole breast was considered most useful as it can reduce hotspot and improve overall cosmesis.

Reduction in lung dose, heart dose, contralateral breast dose, and 5 mm thick skin dose are clinically relevant and significant. Postradiation pneumonitis after whole breast radiation is not very common. Reported incidence of radiation pneumonitis is 1%–2%. Although our initial clinical report did not demonstrate any adverse impact on lung function or features of pneumonitis using single arc VMAT plan, we considered this further reduction of lung dose a potential gain from using dual arcs. The unreported data from the earlier study did not reveal any clinical sign or symptoms of radiation pneumonitis.

Another potential positive impact is a reduction of mean heart dose and heart volume receiving 25 and 18 Gy. Radiation-induced cardiac morbidity is a big concern as most of these early breast cancer patients will be a long-term survivor. It is established that with increase in every 1 Gy of mean cardiac dose, risk of long-term major cardiac events increases by 7.4% without any established minimum threshold of the dose.[10] Mean heart dose was reduced from 4.56 to 2.81 Gy which is relevant for future clinical outcome. The current study does not intend to show any benefit in terms of any clinical events; however, it clearly shows some expected further reduction of cardiac morbidity.

Maximum and mean dose to contralateral breast were also reduced significantly (32.55 vs. 18.58 Gy and 5.81 vs. 1.72 Gy, respectively). This high Dmax may seem unusual. It was postulated that absence of PTV editing could lead to such high contralateral breast Dmax in a patient with large breast volume where the medial border for both breasts can be very close.

Postradiation rib fracture is a known long-term complication of breast irradiation. Different studies published in recent past has estimated the risk of radiation-induced rib fracture to be 4%–5% and higher dose increased the risk of fracture.[11],[12],[13] Dual arcs reduced mean dose of ribs from 23.40 to 17.41 Gy (P = 0.001).

Using two partial arcs VMAT for planning whole breast irradiation and simultaneous integrated boost with an accelerated hypofractionation scheme is rare in medical literature. In a recent dosimetric study of two different techniques of dual partial arcs for left-sided breast cancer, Fogliata et al. have demonstrated reduction of high dose spill to normal tissue and a reduction of mean dose to critical structures using different planning strategies.[14] In this study, two different strategies, namely, RA_avoid and RA_full were used to plan 40.5 Gy to the whole breast in 15 fractions. RA_full could achieve better conformity and reduction of high dose spillage to normal tissue and skin. RA_avoid significantly reduced mean dose to critical structures including heart, ipsilateral lung, contralateral lung, and contralateral breast (P < 0.001). This study is impressive; however, it cannot be compared with the present study as we have used simultaneous integrated boost to lumpectomy cavity.

Liu et al.[15] has compared single arc VMAT, dual arc VMAT and intensity modulated radiotherapy (IMRT) techniques for adjuvant radiation after breast conservation to whole breast with simultaneous integrated boost to lumpectomy cavity. Whole breast and lumpectomy cavity were planned with simultaneous integrated boost technique to a dose of 50 and 60 Gy in 25 daily fractions of 2 and 2.4 Gy, respectively. Single arc and dual arc plans were superior to IMRT plans in terms of target coverage, CI, and homogeneity index (HI). This study showed improved OAR dosimetry with VMAT compared to IMRT and dual arc VMAT significantly improved almost all OAR dosimetry. This study has used softer dose constraints for lung which was much more stringent in our study. Dose and fractionation schedule was also not comparable to our study protocol. In our patients, lumpectomy cavity volume was larger. These factors played a significant role in achieving planning targets. Furthermore, it was not clear whether a margin around lumpectomy cavity was used to create CTV boost in the study by Liu et al. The study protocol mandated using 1.5 cm margin around lumpectomy cavity as we considered this as area with the highest risk of tumor recurrence.

In another study with postmastectomy patients, Zhao et al. have compared single arc VMAT, dual arc VMAT and IMRT plans of 50 Gy in 25 fractions.[16] Target volume includes postoperative chest wall, supraclavicular and internal mammary lymph nodes. Eventually, the dose constraints were completely different than what were used in our study. However, this study also showed improvement in HI and CI with dual arcs over single arc. Other dose parameters were comparable between single and dual arcs.

Virén et al. in their study of four different radiation techniques for left-sided breast cancer have compared field in field (FinF), tangential IMRT (tIMRT), tangential VMAT (tVMAT), and continuous VMAT (cVMAT).[17] 50 Gy in 25 fractions were planned. They have used two dual arcs for tVMAT plan and one dual arc for cVMAT plan. Both IMRT and VMAT achieved better HI compared to FinF. Both dual VMAT techniques achieved better HI compared to tIMRT. Dose coverage was significantly better with VMAT techniques compared to IMRT. VMAT also reduced mean cardiac dose, V30 and V25 of heart and LAD; mean dose and V20 of ipsilateral lung when compared with FinF or tIMRT. This study proved overall superiority of different dual arc VMAT techniques over IMRT or FinF techniques but has not compared single arc versus dual arc technique and dose fractionation scheme was also different. No boost was planned in this study which made planning and optimization easier.

We could not find studies with similar dose fractionation, target definition and/or planning criteria comparable to our study. Dose fractionation in our study is completely different, and we used more stringent criteria for few OARs. For complex planning technique, each parameter or constraint can pose challenge in achieving the goals. This dosimetric study clearly indicates the benefit of using dual partial arcs instead of one. A reduction in D2cc of whole breast PTV will reduce developing hotspot which is expected to provide better short- and long-term skin toxicity and cosmesis. Ipsilateral and contralateral lung dose reduction can reduce the chance of long-term pulmonary complication. Similarly, reduced cardiac dose will benefit patients from reduced long-term cardiac morbidity. Chance of long-term risk of rib fracture can also be reduced with a reduction of dose to ribs. Contralateral breast dose was also reduced with dual arc technique which has always been considered as a risk factor for developing secondary malignancy. In the absence of any clear dose-response effect of contralateral breast dose and second malignancy, this further reduction in radiation dose to contralateral breast can be considered as additional gain. Dose to skin was also reduced which can lead to better cosmesis. Like any dosimetric study, this study also lacks clinical outcome. We believed that dosimetric study should be the foundation for future clinical study. This present dosimetric study showed potentially better clinical outcome.


 > Conclusion Top


Accelerated hypofractionation with simultaneous integrated boost to lumpectomy cavity for early breast cancer using VMAT is relatively sparse in literature. In the absence of any available evidence showing dosimetric benefit of dual partial arcs over single arc to achieve planning goals, this study can be of immense value. We started with skepticism but could achieve few benefits which might have long-term clinical significance. With early breast cancer becoming more curable, long-term complications and survivorship are also becoming more relevant. We believe from history of radiation oncology that technological advancement and its use in clinical practice would be ever increasing. Thus, it becomes more important to have a clear idea about risks and benefits of newer techniques. Given complex nature of this treatment, it is advisable not to use this technique for routine treatment in the absence of proper experience and expertise. Furthermore, our study consisted of 15 patients. This can be a potential source of statistical error which needs to be taken care of when accepting this result for clinical use. We strongly recommend performing dosimetric study in respective department to understand the limitations and set their own goal for future clinical application.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Veronesi U, Cascinelli N, Mariani L, Greco M, Saccozzi R, Luini A, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347:1227-32.  Back to cited text no. 1
    
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Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R, Parpia S, et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med 2010;362:513-20.  Back to cited text no. 2
    
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Yarnold J, Ashton A, Bliss J, Homewood J, Harper C, Hanson J, et al. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: Long-term results of a randomised trial. Radiother Oncol 2005;75:9-17.  Back to cited text no. 3
    
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START Trialists' Group; Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK standardisation of breast radiotherapy (START) trial A of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet Oncol 2008;9:331-41.  Back to cited text no. 4
    
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START Trialists' Group; Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ, et al. The UK standardisation of breast radiotherapy (START) trial B of radiotherapy hypofractionation for treatment of early breast cancer: A randomised trial. Lancet 2008;371:1098-107.  Back to cited text no. 5
    
6.
FAST Trialists Group; Agrawal RK, Alhasso A, Barrett-Lee PJ, Bliss JM, Bliss P, et al. First results of the randomised UK FAST trial of radiotherapy hypofractionation for treatment of early breast cancer (CRUKE/04/015). Radiother Oncol 2011;100:93-100.  Back to cited text no. 6
    
7.
Mondal D, Julka PK, Sharma DN, Jana M, Laviraj MA, Deo SV, et al. Accelerated hypofractionated adjuvant whole breast radiation with simultaneous integrated boost using volumetric modulated arc therapy for early breast cancer: A phase I/II dosimetric and clinical feasibility study from a tertiary cancer care centre of India. J Egypt Natl Canc Inst 2017;29:39-45.  Back to cited text no. 7
    
8.
Breast Cancer Atlas. Available from: http://www.rtog.org/CoreLab/ContouringAtlases/LungAtlas.aspx. [Last accessed on 2017 Oct 12].  Back to cited text no. 8
    
9.
Plataniotis GA, Dale RG. Biologically effective dose-response relationship for breast cancer treated by conservative surgery and postoperative radiotherapy. Int J Radiat Oncol Biol Phys 2009;75:512-7.  Back to cited text no. 9
    
10.
Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Brønnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013;368:987-98.  Back to cited text no. 10
    
11.
Shanley S, McReynolds K, Ardern-Jones A, Ahern R, Fernando I, Yarnold J, et al. Late toxicity is not increased in BRCA1/BRCA2 mutation carriers undergoing breast radiotherapy in the United Kingdom. Clin Cancer Res 2006;12:7025-32.  Back to cited text no. 11
    
12.
Smith GL, Xu Y, Buchholz TA, Giordano SH, Jiang J, Shih YC, et al. Association between treatment with brachytherapy vs. whole-breast irradiation and subsequent mastectomy, complications, and survival among older women with invasive breast cancer. JAMA 2012;307:1827-37.  Back to cited text no. 12
    
13.
Galland-Girodet S, Pashtan I, MacDonald SM, Ancukiewicz M, Hirsch AE, Kachnic LA, et al. Long-term cosmetic outcomes and toxicities of proton beam therapy compared with photon-based 3-dimensional conformal accelerated partial-breast irradiation: A phase 1 trial. Int J Radiat Oncol Biol Phys 2014;90:493-500.  Back to cited text no. 13
    
14.
Fogliata A, Seppälä J, Reggiori G, Lobefalo F, Palumbo V, De Rose F, et al. Dosimetric trade-offs in breast treatment with VMAT technique. Br J Radiol 2017;90:20160701.  Back to cited text no. 14
    
15.
Liu ZM, Ge XL, Chen JY, Wang PP, Zhang C, Yang X, et al. Adjuvant radiotherapy after breast conserving treatment for breast cancer: A Dosimetric comparison between volumetric modulated arc therapy and intensity modulated radiotherapy. Asian Pac J Cancer Prev 2015;16:3257-65.  Back to cited text no. 15
    
16.
Zhao LR, Zhou YB, Sun JG. Comparison of plan optimization for single and dual volumetric-modulated arc therapy versus intensity-modulated radiation therapy during post-mastectomy regional irradiation. Oncol Lett 2016;11:3389-94.  Back to cited text no. 16
    
17.
Virén T, Heikkilä J, Myllyoja K, Koskela K, Lahtinen T, Seppälä J, et al. Tangential volumetric modulated arc therapy technique for left-sided breast cancer radiotherapy. Radiat Oncol 2015;10:79.  Back to cited text no. 17
    



 
 
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