A dosimetric comparison of Volumetric Modulated Arc Therapy (VMAT) and High Dose Rate (HDR) brachytherapy in localized cervical cancer radiotherapy

Abstract

BACKGROUND:

Cervical cancer radiotherapy is usually administrated through 3-Dimensional Conformal Radiation Therapy (3DCRT) followed by a brachytherapy (BT) boost.

PURPOSE:

To investigate whether Volumetric Modulated Arc Therapy (VMAT) can replace High Dose Rate (HDR) intracavitary BT boost for patients undergoing cervical cancer radiotherapy.

MATERIALS AND METHODS:

Computed Tomography (CT) images for ten patients with tandem and ovoids were included in this study. Target volumes, rectum, bladder, sigmoid, small bowel and both femoral heads were delineated. Two plans were carried out including (a) a BT plan optimized manually by modifying dwell time and Ir-192 source positions, (b) a VMAT plan generated using two partial arcs with 10 MV photon beam. The prescribed dose was 7 Gy. The relevant dose volume parameters (DVPs) of target volumes and OARs for the two plans were analyzed statistically using SPSS Wilcoxon Signed Rank test.

RESULTS:

VMAT plan showed a significant reduction of 9.1%, 9.3%, 15.4%, 14.4% and 13.1% in rectum maximum dose, rectum D_2cc, bladder maximum dose, bladder D_2cc and sigmoid maximum dose (P < 0.05). VMAT and BT plans showed comparable D_2cc of sigmoid and small bowel maximum doses (P = 0.333 and P = 0.646). On the other hand, VMAT showed significantly higher small bowel D_2cc and maximum point dose for both femoral heads comparing to BT plan (P < 0.05). Also, VMAT plan yielded greater homogeneous target coverage compared to BT plan (P < 0.05).

CONCLUSION:

The study demonstrated that VMAT plan achieves significant dose reduction of rectum, bladder and sigmoid, as well as superior homogeneous target coverage compared to BT plan. On the other hand, VMAT delivers more radiation exposures to small bowel and femoral heads.

Keywords

Cervical cancer high dose rate Volumetric Modulated Arc Therapy intracavitary brachytherapy

1. Introduction

The currently recommended treatment approach of cervical cancer radiotherapy consists of an external beam radiation therapy to the whole pelvis with a total dose of 45 or 50 Gy, followed by intracavitary brachytherapy boost to the primary tumor [1 –3]. The brachytherapy has the advantages of maximizing the dose within the tumor with rapid fall-off of the dose outside the tumor in order to protect the surrounding normal tissues and preserve the organ at risks (OAR) [4, 5]. On the other hand, brachytherapy is considered as painful invasive technique, which often requires spinal or general anesthesia [6]. It may also show some complications during the application of the apparatus as uterine perforation, infection and bleeding. In addition, brachytherapy may lead to late complications and toxicities of rectum, bladder, small bowel and vagina [7 –10].

Several previous studies have attempted to mimic brachytherapy boost, using external photon beam techniques such as; Three-Dimensional Conformal Radiation Therapy (3DCRT), Intensity-Modulated Radiation Therapy (IMRT), Helical Tomotherapy (HT) and Volumetric Modulated Arc Therapy (VMAT) [11 –13]. VMAT is a newer approach of IMRT planning that delivers the radiation dose by continuous rotation of gantry around the patient in one or more arcs [14]. The cone beam is modulated by the variation of gantry speed, beam aperture shape via movement of the multi-leaf collimator leaves (MLC) and so the dose rate [14, 15].

VMAT has superior dosimetric advantages over IMRT such as significant treatment time reduction with fewer monitor units (MUs) which in turn increases patient comfort and reduces patient motion and internal organ’s displacement during treatment [14]. VMAT also shows highly conformal dose distributions, uncompromised target coverage with significant rectum and bladder sparing [16, 17].

In light of the above risks of brachytherapy and the benefits of VMAT compared to other techniques, this study aimed to investigate whether VMAT can replace HDR intracavitary BT boost for patients undergoing cervical cancer radiotherapy.

2. Materials and methods

This study is a retrospective analysis for ten patients previously diagnosed with localized cervical cancer. They were referred to radiation therapy department, King Abdul-Aziz University Hospital between 2016 and 2017 for primary chemoradiotherapy. The average age of the patients was 55.6 years (range, 33 to 73 years). The patient characteristics are shown in Table 1. This research was ethically approved by the Unit of Biomedical Ethics in King Abdul-Aziz University (Reference No, 475-16).

Table 1
Patient characteristics

Histology Number of patients

Squamous cell carcinoma 9

Adenocarcinoma 1

FIGO stage

IIA2 1

IIB 5

IIIB 4

Histology	Number of patients
Squamous cell carcinoma	9
Adenocarcinoma	1
FIGO stage
IIA2	1
IIB	5
IIIB	4

FIGO = International Federation of Gynaecology and Obstetrics.

All patients had received external beam radiotherapy to the whole pelvis (four-field box technique) with prescribed dose of 45 Gy (1.8 Gy / fraction). The patients with tandem and ovoids were scanned on CT simulator (Siemens Somatom Emotion, Erlangen, Germany) in supine positions with 2 mm slice thickness. Scan started superior from the fifth lumbar vertebra to approximately one-third of the femur diaphysis. CT scan images were transferred to Eclipse treatment planning system (Varian Medical Systems Inc., Palo Alto, CA) where target volumes and OARs werecontoured.

Target volumes including; high risk clinical target volume (HR-CTV) and intermediate risk clinical target volume (IR-CTV) were outlined according to the gynaecological Groupe Européen de Curiethérapie European Society for Therapeutic Radiology and Oncology (GYN GEC-ESTRO) recommendations for BT planning. For VMAT planning, the planning target volumes (PTVs) including HR-PTV and IR-PTV were created by adding 5 mm margin around HR-CTV and IR-CTV respectively. Organs at risk (OARs) including rectum, bladder, sigmoid, small bowel and both femoral heads were contoured according to Radiation Therapy Planning Oncology Group (RTOG) protocol of pelvis. For each patient two plans were generated; HDR brachytherapy (BT) and VMAT plans.

In brachytherapy treatment planning, the DRR images were reconstructed in order to check the applicator geometry. The positions of Ir-192 source in tandem and ovoids were activated manually with a step size of 0.5 cm. The first dwell position in the tandem started at 1-cm inferior from the tip and stopped at 1-cm superior to the surface of the ovoids. The first dwell position of each ovoid activated at 0.5 cm depth from the tip. The total dwell positions were 5 to 7 positions in each ovoid and 8 to 11 positions in the tandem. The dose distribution normalized initially to point A. Then, the dose distribution was optimized manually by modifying the dwell times and/ or the source positions in order to achieve sufficient sparing of OARs with adequate target coverage.

VMAT plans were carried out with 10 MV photon beam using two partial arcs. The gantry angle for each arc started from 110° to 250° in a counter clockwise rotation. In order to minimize MLC tongue and groove effect, the collimator was fixed at 30° for first arc and 330° for the second arc. The isocenter was positioned at the center of HR-PTV. The treatment plan optimization was performed by filling the optimization set up table with the dose volume constraints (DVCs). These DVCs were initially taken from several studies then were modified in many trails in order to find the optimum plan [6 , 19]. Table 2 illustrates the DVCs used for optimization of VMAT plans.

Table 2

Optimization set up table used for VMAT plans

Structure	Type	Volume (%)	Dose (Gy)
HR-PTV	Upper	0	8.4
	Lower	100	7
IR-PTV	Upper	0	6.7
	Lower	100	5.6
Bladder	Upper	0	4.9
Bladder-PTVs	Upper	50	3.5
		40	4.2
		0	4.9
Rectum	Upper	0	2.8
Rectum-PTVs	Upper	50	1.4
		35	2.1
		0	2.8
Small Bowel	Upper	0	4.2
		30	3.5
		50	2.8
Sigmoid	Upper	0	3.5
Femoral Heads	Upper	0	1.4

HR-PTV = High Risk Planning Target Volume, IR-PTV =Intermediate Risk Planning Target Volume, Rectum-PTVs = Rectum excluding PTVs, Bladder-PTVs = Bladder excluding PTVs.

The dose prescribed by the clinical oncologist was 7 Gy. Our objectives were; 90% of HR volumes (D_90 %) should receive the prescribed dose (7 Gy) while the 90% of IR volumes should be covered by 75% of prescribed dose (5.2 Gy) [20, 21]. Then the dose distributions and dose volume histograms (DVHs) were generated for all patients. Targets coverage was assessed by D_90 % and D_95 % (dose to 90% and 95% of the volume). Dose homogeneity within target volumes was assessed by homogeneity index (HI, calculated as D_5 %/D_95 %) [22]. Regarding to OARs; rectum, bladder, sigmoid and small bowel sparing was evaluated by D_2cc (dose to 2cc of volumes) and the maximum point dose. In addition, femoral head sparing was evaluated by maximum point dose.

Then, we performed statistical data analysis. Specifically, in this study, the relevant dose volume parameters (DVPs) of target volumes, rectum, bladder, sigmoid, small bowel and femoral heads for BT and VMAT plans were compared and analyzed statistically using Wilcoxon Signed Rank test of SPSS version 23 (SPSS, Chicago, IL). A P-value of significance level of 0.05 was used.

3. Results

This study consisted of 10 patients with advanced cervical carcinoma. Table 3 shows the average values of the volume of HR-CTV, IR-CTV, HR-PTV and IR-PTV.

Table 3
The Average values of the volume of HR-CTV, IR-CTV, HR-PTV and IR-PTV

Structure Mean (cc) Range (cc)

HR-CTV 43.6 18.8–68.2

IR-CTV 107.1 33.8–153.2

HR-PTV 76.8 37.1–114.4

IR-PTV 163.5 65.1–244.6

Structure	Mean (cc)	Range (cc)
HR-CTV	43.6	18.8–68.2
IR-CTV	107.1	33.8–153.2
HR-PTV	76.8	37.1–114.4
IR-PTV	163.5	65.1–244.6

HR-CTV = High Risk Clinical Target Volumes; IR-CTV =Intermediate Risk Clinical Target Volumes; HR-PTV = High Risk Planning Target Volume, IR-PTV = Intermediate Risk Planning Target Volume.

In assessing target dose coverage and dose homogeneity, the PTV coverage was superior with VMAT plans compared to BT plans. This was demonstrated by 95%, 90% and 80% isodose wash that match well the PTV shape in VMAT plans while the CTVs are under-dosed in BT plans (Fig. 1). Table 4 gives the statistical analysis and DVPs for high risk and intermediate risk target volumes comparing VMAT and BT plans. Target coverage was superior with VMAT plans compared to BT plans as VMAT plans showed significantly higher values of D_95 % for high risk and intermediate risk volumes compared to BT plans (P = 0.017 and 0.012), while the average values of D_90 % of both plans were comparable (P = 0.475 and 0.333). The dose homogeneity within the target volumes was significantly better with VMAT plans than with BT plans as VMAT plans showed significantly lower HI than BT plans (P = 0.005 and 0.005).

Table 4

Relevant dose volume parameters of high risk and intermediate risk target volumes in Gy comparing BT and VMAT plans

DVPs	Min	Max	Average	Differences	P- Value
High Risk Target Volumes
D_90 % (BT)	6.43	7.85	6.83	0.02	0.475
D_90 % (VMAT)	6.7	7.03	6.85
D_95 % (BT)	5.78	7.29	6.2	0.47	0.017
D_95 % (VMAT)	6.43	6.92	6.67
HI (BT)	4.17	7.54	5.86	–4.6	0.005
HI (VMAT)	1.21	1.31	1.25
Intermediate Risk Target Volumes
D_90 % (BT)	4.4	6.65	5.43	0.26	0.333
D_90 % (VMAT)	4.86	5.93	5.7
D_95 % (BT)	3.55	6.04	4.7	0.75	0.012
D_95 % (VMAT)	4.52	5.64	5.45
HI (BT)	6.07	10.04	7.28	–5.76	0.005
HI (VMAT)	1.44	1.84	1.51

HI = homogeneity index; The differences = VMAT plans value – BT plans value.

Fig.1

The Dose distribution in axial, sagittal and coronal views comparing VMAT and BT plans. The 95%, 90% and 80% isodose wash shown in red, light blue and dark blue respectively. It also shows HR volumes in brown, IR volume in red, rectum in green and bladder in yellow.

In assessing the dose distribution within organs at risk, Table 5 shows a significant reduction of 9.1% and 9.3% in the average values of rectum maximum point dose and D_2cc with VMAT plans compared to BT plans (P = 0.037 and 0.047) (Fig. 2a). There was also a significant reduction of 15.4%, 14.4% and 13.1% in the average values of bladder maximum point dose, bladder D_2cc and sigmoid maximum point dose with VMAT plans compared to BT plans (P = 0.028, 0.017 and 0.009)(Fig. 2b and c).

Table 5

Relevant dose volume parameters of OARs in Gy comparing BT and VMAT plans

DVPs	Min	Max	Average	Differences	Reduction%	P-Value
Rectum
Max Dose (BT)	4.33	8.13	6.63	–0.67	–9.1	0.037
Max Dose (VMAT)	4.43	6.7	5.95
D_2cc (BT)	2.89	5.55	4.57	–0.47	–9.3	0.047
D_2cc (VMAT)	3.31	5.27	4.09
Bladder
Max Dose (BT)	3.78	12.9	8.37	–1.84	–15.4	0.028
Max Dose (VMAT)	4.1	7.16	6.53
D_2cc (BT)	2.76	7.78	5.78	–0.67	–14.4	0.017
D_2cc (VMAT)	1.45	6.58	5.1
Sigmoid
Max Dose (BT)	5.23	10.9	7.22	–1.07	–13.1	0.009
Max Dose (VMAT)	4.56	7.01	6.14
D_2cc (BT)	3.09	5.94	4.49	0.16	4.8	0.333
D_2cc (VMAT)	3.58	6.01	4.66
Small bowel
Max Dose (BT)	1.04	9.81	5.3	0.2	12.5	0. 646
Max Dose (VMAT)	0.2	7.49	5.5
D_2cc (BT)	0.9	5.16	2.94	0.86	27.5	0.016
D_2cc (VMAT)	0.14	5.78	3.79
RT femoral head
Max Dose (BT)	0.48	1.64	1.15	0.59	42.1	0.017
Max Dose (VMAT)	0.15	2.35	1.75
LT femoral head
Max Dose (BT)	0.8	1.53	1.26	0.81	64.8	0.007
Max Dose (VMAT)	0.56	2.59	2.08

The percentage of reduction is calculated as = $\frac{VMAT plans value - BT plans value}{BT plans value} \times 100$ .

However, the average values of sigmoid D_2cc and small bowel maximum point dose for both plans were comparable (P = 0.333 and 0.646) (Fig. 2c and d). On the other hand, BT showed a significant reduction of 27.5%, 42.1% and 64.8% in the average values of small bowel D_2cc, maximum point dose of the head of right (RT) and left (LT) femur compared to VMAT plans (P = 0.016, 0.017 and 0.007) (Fig. 2d, e and f).

Fig.2

Dose volume histograms for OARs comparing BT and VMAT plans for 6 different patients (a) rectum (b) bladder (c) sigmoid (d) small bowel (e) RT femoral head (f) LT femoral head.

4. Discussion

Patients undergoing cervical cancer radiotherapy are usually treated with the brachytherapy boost technique after three-dimensional conformal external beam approach [1]. The late complications and toxicities of brachytherapy have motivated the studies for evaluating the capability of external beam techniques to mimic brachytherapy [7, 8]. In this regard, current study was undertaken to evaluate the dose distribution of two partial arcs VMAT technique compared to the high dose rate BT technique for ten patients with locally advanced cervical cancer.

First, in assessing target dose coverage and dose homogeneity, this study revealed that VMAT plans achieved superior target coverage (D_95 %) for HR and IR volumes compared to BT plans. These results are in accordance with the results of Caitlin Merrow et al. [17] and Michael C. Dobelbower et al. [23]. On the other hand, the results of the current study are in contrast with the results of Rajni A. Sethi et al. [6] and B. Shwetha et al. [24] who achieved comparable target coverage. In the current study BT and VMAT plans showed no significant differences in the average values of D_90 % for both high risk and intermediate risk volumes. This is because both plans were normalized to provide comparable D_90 % as recommended by the GYN GEC ESTRO working group [20]. In the present study, VMAT plans achieved also better dose homogeneity within high risk and intermediate risk volumes compared to BT plans. This was expected due to the existence of the high dose gradient within the target volumes in BT plans [24].

Second, in assessing the organs at risk sparing, the current study showed significant reductions in rectum maximum point dose and D_2cc with VMAT plans compared to BT plans. The significant reductions in rectum DVPs were attributed to the use of two partial arcs VMAT in order to avoid treatment through the rectum from the posterior direction (The gantry angle started from 110° to 250° in a counter clockwise rotation). The results of the current study are in accordance with the results of Rajni A. Sethi et al. [6]. On the other hand, The above results are in contrast with the results of Dietmar Georg et al. [3] who aimed in their study to achieve comparable doses to OARs. Also our results disagreed with Michael C. Dobelbower et al. [23] as they did not attempt to spare the critical organs^. In Caitlin Merrow et al. [17] study BT plans achieved better rectum sparing compared with VMAT plans. This might be due to using one full arc and two full noncoplanar arcs VMAT.

The current study showed significant reductions in the average values of bladder maximum point dose and bladder D_2cc with VMAT plans compared to BT plans. These results are supported by the results of Rajni A. Sethi et al. [6] study. On the other hand, the results of the current study are in contrast with the results of B. Shwetha et al. [24] and Dietmar Georg et al. [3] studies, as they found that the D_2cc of bladder was comparable to BT plans and IMRT plans.

In addition, in the current study VMAT plans achieved significant reduction in sigmoid maximum point dose compared to BT plans with comparable sigmoid D_2cc values. These results are matched with the results of Dietmar Georg et al. [3] study. Specifically, in the current study both plans achieved comparable values for small bowel maximum point dose. The results of the current study are in contrast with the results of Rajni A. Sethi et al study [6], who found that VMAT plans achieved a significant reduction of small bowel maximum point dose compared to BT plans. Rajni A. Sethi et al. [6] achieved small bowel sparing with VMAT plans because they used harder constrains for small bowel compared with the constraints of the current study (no volume of small bowel should receive more than 2 Gy in their study compared to 4.2 Gy in the current study). In the current study, the D_2cc was also used for small bowel evaluation as recommended by EMBRACE study [25]. In the current study VMAT plans achieved higher D_2cc of small bowel compared with BT plans. This finding is also consistent with Dietmar Georg et al results [3].

In the current study, we also found that the average values of the maximum point dose of femoral heads were significantly higher with VMAT plans compared to BT plans. The higher dose to femoral heads with VMAT plans could be due to more exposure to the normal tissue through beam entry and exit paths. These results are supported by the results of Caitlin Merrow et al. [17] and Rajni A. Sethi et al. [6] studies. Although VMAT plans provides significant dose reduction of rectum, bladder and sigmoid, low dose regions of VMAT may be expanded considerably in the whole body. This is because of the coplanarity of fields and arcs so the beam cross different tissues to irradiate the target volume. On the other hand, for BT, the dose is distributed radially from the center of the sources so large volume of normal tissues is avoided. Thus, in VMAT larger volumes received low doses; whereas in BT, smaller volumes were irradiated with high doses [12, 13]. Previous studies reported that the increase in the volume of tissue with low dose exposure might cause a higher risk of second malignancy [26, 27]. But this issue could be of less importance for patients already treated with external beam radiation.

This research was carried out using the dosimetric evaluation of one fraction level for OARs sparing. However, the patients with localized cervical cancer are usually treated with four fractions of BT added to EBRT with the prescribed dose of 45 Gy/ 25 fractions. So the combined total dose of EBRT and BT (45 Gy/ 25 fractions + 7 Gy X 4 fractions) was calculated using the radiobiological evaluation based on the linear quadratic equivalent dose (EQD₂) [20, 25]. As shown in the next paragraph that the average values of relevant dose volume parameters of rectum, bladder, sigmoid, small bowel and heads of femurs are all within the recommended tolerance.

The average values of rectum D_2cc were 4.57 Gy and 4.09 Gy, leading to an EQD₂ of 70.9 Gy and 66.4 Gy for BT and VMAT plans respectively. This was within the recommend tolerance of 75 Gy. For bladder, the average values of D_2cc were 5.78 Gy and 5.1 Gy, giving an EQD₂ of 83.8 Gy and 76.2 Gy for BT and VMAT plans respectively. Hence, this was under the recommend tolerance of 90 Gy. Moreover, the average values of D_2cc for sigmoid were 4.49 Gy and 4.66 Gy, which are related to EQD₂ of 70.1 Gy and 71.8 Gy for BT and VMAT plans. This was under the recommend maximum of 75 Gy. For small bowel, the average values of D_2cc were 2.94 Gy and 3.79 Gy, leading to an EQD₂ of 57.2 Gy and 63.8 Gy for BT and VMAT plans respectively. This was also within the recommend maximum of 70 Gy [19, 25].

Although several studies have been published compared the external beam radiation therapy techniques such as IMRT or VMAT with HDR brachytherapy technique for cervical cancer, this study has unique characteristic or differences as comparing to the previous studies. Specifically, most of the previously published studies used the traditional approach for the target definition and the dose prescription to point A in brachytherapy planning [6, 17]. On the other hand, the current study used the modern approach for the target definition (HR and IR CTVs) and prescribed the dose to these structures rather than point A in brachytherapy plans. This is of benefit because the dose prescription to point A is unable to specify anatomical structures and obtained uncertainty about whether the tumour volume is covered with the prescribed dose especially in large tumour volumes [21 , 29].

In addition, most of the previous studies defined the PTV in external beam technique as 100 % isodose line from brachytherapy plans [6 , 24]. While, in the current study in VMAT planning, additional margins were added to the CTVs to create the PTVs. This margin was applied in order to reflect the actual volume required to be covered with the dose prescription in external beam techniques (to take into account the setup and internal motion) [30, 31].

In several studies, the constraints applied to OARs were based on the ICRU reference points (rectum and bladder points) and/or maximum point dose [6, 17]. But in the current study, the dose received by certain volume such as D_2cc was also applied as a constraint for OARs sparing because it provides more precise analysis for OARs compared to reference points used in conventional BT plans [21, 29]. Several previous studies also highlighted the importance of achieving comparable target coverage for both plans without attempt to spare the OARs, and vice-versa [3, 24]. The current study has attempted to achieve adequate target coverage with minimizing the dose to OARs below their tolerance values during the optimization process. Hence, these considerations may correlate with more practical and meaningful results. Finally, although this study included small patient population, it may not affect the validity of statistical analysis [32, 33].

Conclusion

Footnotes

Acknowledgments

The authors would have extended gratitude to Varian Medical System members for providing the Eclipse planning system, continuous help and technical support throughout the work. The authors would like to thank King Abdul-Aziz University Hospital members specially Mr, Meteb Alghamwa (medical physicist) for providing the CT scan images and support throughout the work.

References

Vordermark , Radiotherapy of cervical cancer, Oncology research and treatment 39(9) (2016), 516–520.

Kaidar-Person , et al., Current principles for radiotherapy in cervical cancer, Medical Oncology 29(4) (2012), 2919–2922.

Georg , et al., Image-guided radiotherapy for cervix cancer: High-tech external beam therapy versus high-tech brachytherapy, International Journal of Radiation Oncology* Biology* Physics 71(4) (2008), 1272–1278.

A.V.

D’Amico , et al., Real-time magnetic resonance image-guided interstitial brachytherapy in the treatment of select patients with clinically localized prostate cancer, International Joournal of Radiation Oncology Biology Physics 42(3) (1998), 507–515.

Nag , High dose rate brachytherapy: Its clinical applications and treatment guidelines, Technology in cancer research & treatment 3(3) (2004), 269–287.

Sethi , et al., Is there a role for an external beam boost in cervical cancer radiotherapy? Frontiers in Oncology 3(3) (2013), 1–6.

Potter , et al., Definitive radiotherapy based on HDR brachytherapy with iridium 192 in uterine cervix carcinoma: Report on the Vienna University Hospital findings (1993-1997) compared to the preceding period in the context of ICRU 38 recommendations, Cancer/Radiothérapie 4(2) (2000), 159–172.

Liu , et al., High dose rate versus low dose rate intracavity brachytherapy for locally advanced uterine cervix cancer, Cochrane Database of Systematic Reviews 2014(10).

B.G.

Clark , et al., Rectal complications in patients with carcinoma of the cervix treated with concomitant cisplatin and external beam irradiation with high dose rate brachytherapy: A dosimetric analysis, International Journal ofRadiation Oncology* Biology* Physics 28(5) (1994), 1243–1250.

10.

S.-W.

Chen , et al., The adverse effect of treatment prolongation in cervical cancer byhigh-dose-rate intracavitary brachytherapy, Radiotherapy and Oncology 67(1) (2003), 69–76.

11.

Kilic ,

Cracchiolo and

Mahmoud , Non-brachytherapy alternatives in cervical cancer radiotherapy: Why not? Appl Radiat Oncol 4(4) (2015), 11–17.

12.

Pedicini , et al., Comparative dosimetric and radiobiological assessment among a nonstandard RapidArc: Standard RapidArc, classical intensity-modulated radiotherapy, and 3D brachytherapy for the treatment of the vaginal vault in patients affected by gynecologic cancer, Medical Dosimetry 37(4) (2012), 347–352.

13.

Pedicini , et al., Local tumor control probability to evaluate an applicator-guided volumetric-modulated arc therapy solution as alternative of 3D brachytherapy for the treatment of the vaginal vault in patients affected by gynecological cancer, Journal of applied clinical medical physics 14(2) (2013), 146–157.

14.

Elith , et al., An introduction to the intensity-modulated radiation therapy (IMRT) techniques: Tomotherapy, and VMAT, Journal of Medical Imaging and Radiation Sciences 42(1) (2011), 37–43.

15.

F.M.

Khan and

J.P.

Gibbons , Intensity-Modulated radiation therapy, in Khan's the physics of radiation therapy, Khan,

F.M.

Gibbons,

J.P.

Editors. 2014, Wolters Kluwer Health, pp. 430–453.

16.

N.M.

Sedeh , Dosimetric and radiobiological comparison of Forward Tangent Intensity Modulated Radiation Therapy (FT-IMRT) and Volumetric Modulated Arc Therapy (VMAT) for early stage whole breast cancer, in The Charles E. Schmidt College of Science, Florida Atlantic University: Boca Raton, 2015, p. 79.

17.

Merrow ,

deBoer and

M.B.

Podgorsak , VMAT for the treatment of gynecologic malignancies for patients unable to receive HDR brachytherapy, Journal of Applied Clinical Medical Physics 15(5) (2014), 66–73.

18.

Cozzi , et al., A treatment planning study comparing volumetric arc modulation with RapidArc and fixed field IMRT for cervix uteri radiotherapy, Radiotherapy and oncology 89(2) (2008), 180–191.

19.

Trnková , et al., A detailed dosimetric comparison between manual and inverse plans in HDR intracavitary/interstitial cervical cancer brachytherapy, Journal of contemporary brachytherapy 2(4) (2010), 163–170.

20.

Pötter , et al., Recommendations from gynaecological (GYN) GEC ESTRO working group (II): Concepts and terms in 3D image-based treatment planning in cervix cancer brachytherapy—3D dose volume parameters and aspects of 3D image-based anatomy, radiation physics, radiobiology, Radiotherapy and Oncology 78(1) (2006), 67–77.

21.

TS and

MK , High dose rate brachytherapy of carcinoma of the cervix: Applicability of various dosimetry systems and guidelines in the dose prescription and treatment planning, Austin J Radiat Oncol & Cancer 2(1) (2016), 1–5.

22.

Helal and

Omar , Homogeneity index: Effective tool for evaluation of 3DCRT, Pan Arab Journal of Oncology 8(2) (2015), 20–24.

23.

M.C.

Dobelbower , et al., Dosimetric comparison of IMRT to HDR intracavitary brachytherapy for cervical cancer, Brachytherapy 6(2) (2007), 84.

24.

Shwetha , et al., Dosimetric comparison of high dose rate brachytherapy and intensity-modulated radiation therapy for cervical carcinoma, Journal of Medical Physics/Association of Medical Physicists of India 36(2) (2011), 111–116.

25.

Tanderup , et al., Image guided intensity modulated External beam radiochemotherapy and MRI based adaptive BRAchytherapy in locally advanced CErvical cancer (EMBRACE-II), EMBRACE II Study Protocol, 2015, p. 10.

26.

E.J.

Hall and

C.-S.

Wuu , Radiation-induced second cancers: The impact of 3D-CRT and IMRT, International Journal of Radiation Oncology* Biology* Physics 56(1) (2003), 83–88.

27.

J.A.

Purdy , Dose to normal tissues outside the radiation therapy patient's treated volume: A review of different radiation therapy techniques, Health physics 95(5) (2008), 666–676.

28.

K.H.

Shin , et al., CT-guided intracavitary radiotherapy for cervical cancer: Comparison of conventional point A plan with clinical target volume-based three-dimensional plan using dose-volume parameters, International Journal of Radiation Oncology* Biology* Physics 64(1) (2006), 197–204.

29.

Onal , et al., Comparison of conventional and CT-based planning for intracavitary brachytherapy for cervical cancer: Target volume coverage and organs at risk doses, Journal of Experimental & Clinical Cancer Research 28(1) (2009), 95–105.

30.

J.C.

Stroom and

B.J.

Heijmen , Geometrical uncertainties: Radiotherapy planning margins, and the ICRU-62 report, Radiotherapy and oncology 64(1) (2002), 75–83.

31.

P.C.

Park , et al., A beam-specific planning target volume (PTV) design for proton therapy to account for setup and range uncertainties, International Journal of Radiation Oncology* Biology* Physics 82(2) (2012), 329–336.

32.

F.S.

Nahm , Nonparametric statistical tests for the continuous data: The basic concept and the practical use, Korean Journal of Anesthesiology 69(1) (2016), 8–14.

33.

R.V.

Hogg and

E.A.

Tanis , Probability and statistical inference. 2009: Pearson Educational International.