Dosimetric and biological comparison of treatment plans between EDGE and CyberKnife systems in stereotactic body radiation therapy for localized prostate cancer

doi:10.21203/rs.3.rs-42811/v1

Download PDF

Research

Dosimetric and biological comparison of treatment plans between EDGE and CyberKnife systems in stereotactic body radiation therapy for localized prostate cancer

https://doi.org/10.21203/rs.3.rs-42811/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Aims: The aim of this study was to make a quantitative comparison of plan quality between MLC-based EDGE system and the cone-based CyberKnife system in stereotactic body radiation therapy (SBRT) for patients with localized prostate cancer.

Materials and methods: Ten patients with prostate volumes ranging from 34.65 to 82.16 cc were used for prostate SBRT. Treatment plans were created for both EDGE and CyberKnife G4 systems using the same dose-volume constraints. Dosimetric indices including Planning Tumor Volume (PTV) coverage, conformity index (CI), new conformity index (nCI), homogeneity index (HI), gradient index (GI) were applied for target, while the sparing of critical organs, including bladder, rectum, femoral heads, urethra, penile bulk and normal tissue outside PTV), were evaluated interms of various dose-volume metrics and integral dose (ID). Meanwhile, the required delivery time and number of monitor units (MUs) during irradiation were measured to estimate the treatment efficiency. The radiobiological indices such as equivalent uniform dose (EUD), tumor control probability (TCP) and the normal tissue complication probability (NTCP) were also analyzed.

Results: All dose constraints were achieved by both systems. It showed that the DEGE plans results were closest to the CK plans results in terms of PTV coverage, HI and GI. For EDGE, more conformal dose distribution in the target as well as reduced exposure of critical organs were obtained together with reduction of 91% delivery time and 72% monitor units. EDGE plans also got lower EUD for bladder, rectum, urethra and penile bulk, which associated with reduction of NTCPs. However, higher values of EUD and TCP for tumor were obtained with CK plans.

Conclusions: Our study indicated that both systems were capable of producing almost equivalent plan quality and can meet clinical requirements. CyberKnife G4 system has higher target dose while EDGE system has more advantages based on the considerations of normal tissue sparing and delivery efficiency. With abundant clinical experience, CK provides accurate SBRT treatment with high quality. EDGE system also can be considered to be an option for SBRT treatment for localized prostate cancer treatment.

Oncology

Cancer Biology

Stereotactic body radiotherapy

Prostate cancer

CyberKnife

EDGE.

Stereotactic Body Radiation Therapy (SBRT), or Stereotactic Ablative Radiotherapy (SABR) has grown up to be a significant treatment modality for several years, as an alternative of the conventional radiotherapy in prostate cancer [1–4]. Especially, SBRT has been recognized as an appropriate option in cases of localized prostate cancer [5–9]. The radiobiological rational for prostate SBRT is due to its relatively lower α/β ratio (been estimated at 1.5 Gy) than adjacent organs at risk (OARs), which implies the gains in cost effectiveness and biologically equivalent dose to large fractionated radiotherapy [10–12]. Trials have reported superior biochemical control outcomes for patients with prostate cancer by hypo-fractionation [1–4]. SBRT for prostate cancer was recommended as an alternative to conventionally fractionated regiments according to ASTRO model policy update of 2013, as well as National Comprehensive Cancer Network (NCCN) guidelines on prostate version 2.2014. There remains however the technical limitations in the delivery of such high doses due to the proximity of sensitive normal tissues and organs. Therefore, more conformal radiation and sharper dose fall-off outside the targets are necessary in order to deliver such high dose safely.

Currently, multiple techniques available are developed for SBRT treatments [13, 14], among which CyberKnife® (Accuray Inc., Sunnyvale CA) system has been known as one of the predominant SBRT facilities applied in the treatment of prostate cancer [14]. CyberKnife (CK) is a frameless image-guided radiotherapy system involving a 6-MV FFF (Flattening Filter Free) linear accelerator mounted on a flexible robotic arm, which makes it capable of delivering radiation from hundreds of non-coplanar directions. Moreover, its fiducial tracking technique allows for real-time tumor position and motion corrections during prostate SBRT treatment. These capabilities would make it produce improved conformal isodose with high precision [15].

Meanwhile, LINAC, using multileaf collimator (MLC), can also be used for SBRT by either intensity-modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) [16]. EDGE® (Varian Medical Systems, Palo Alto, CA), an update version of TrueBeam, is one of the typical LINAC-based SBRT system. This dedicated machine is equipped with the HD (High definition) 120 leaf MLC (Multi Leaf Collimator), with two modes of FF (Flattening Filter) and FFF beam delivery [17–18]. The MLC leaf resolution improvement with 2.5 mm leaf widths which allows more conformal dose delivery to the target. This system is equipped with multiple imaging modalities for treatment localization.

In order to make it clear which technique is superior, many comparative studies have been carried out between the LINAC and CK system for prostate SBRT [16, 19–21].. However, there is no study directly comparing the characteristics of dose distribution of treatment plans between EDGE and CK. Therefore, it is essential to make a further study on the properties about emerging treatment technology of EDGE system for making an appropriate option for individualized SBRT treatment.

In our study, we performed a comprehensive evaluation of plan quality with the dose performance of EDGE compared to CK SBRT plans for prostate cancer. These comparison results were implemented by adopting some physical and radiobiological indices according to the dose volume histograms (DVHs) calculated on the evaluation software framework developed by our group. The final analyzed results can be used to find out virtues and shortcomings in optimized plans of each technique for making the most appropriate choice in prostate SBRT treatment. Besides, the monitor units (MUs) used and the beam-on times were also compared to examine the delivery efficiency for both systems.

2.1 Case selection and volume definition

Ten patients with localized prostate cancer staged T1-T2b treated using CK SBRT at our institution between 2018 and 2019 were enrolled randomly. Each patient was scanned in head first-supine position, with a full bladder and an empty rectum. Computed tomography (CT) simulation was performed on a Brilliance™ Big Bore 16-slice CT scanner (Philips, Amsterdam, the Netherlands) with a slice thickness of 1.5 mm. Clinical target volume (CTV) and critical structures were contoured jointly by oncologist and radiologist based on the fusion of CT and magnetic resonance (MR) images on the MultiPlan® system (Accuray Inc., Sunnyvale CA; version 4.02). CTV was defined as the whole prostate gland, with sizes of 59.15 ± 15.63 cc (median, 61.48 cc). Planning Target Volume (PTV) was expanded from CTV with a 5 mm isotropic margin, except 3 mm posteriorly according to the literature [1, 2], with sizes of 98.25 ± 23.65 cc (median, 106.47 cc). Organs at risk (OARs) including bladder, rectum, small bowel, femoral heads, penile bulb, and urethra were contoured. The planning CT together with contours mentioned above were transferred to the Varian Eclipse® system (Varian Medical Systems, Palo Alto, CA; version 13.5) for EDGE planning.

2.1 Treatment planning

Two sets of plans were produced with the same CT images and delineated structures. For the purpose of comparison, all the plans were required to prescribe the same dose of 36.25 Gy delivered in 5 fractions and the prescription dose corresponds 100% non-normalized isodose. Dose constraints were set based on the criteria of the RTOG-0938 and previous studies [1, 3, 7, 22]. Required planning constraints are detailed in Table 1. The CK plans were carried out with Multiplan® version 4.0.2 using sequential optimization method. A 6 MV FFF photon beam was employed with a dose rate of 800 MU/min and one or two cones with size of 20 ~ 30 mm. The plans were optimized with sequential process based on the ray tracing algorithm (RTA). Besides, 5 ‘shells’ expanded isotropically from PTV were used to make steep dose fall-off gradient. At the end of the optimization, beams and time reduction were used to make the plan clinically practical. The VMAT plans were produced for EDGE system with the Eclipse version 13.5 using two full 360◦ arcs with the same isocenter located at the geometric center of PTV. The 10MV FFF photon beams at a high dose rate of 2400 MU/min were used in the optimization [17, 23]. The plans were optimized with progressive resolution optimizer (PRO) and calculated with the analytical anisotropic algorithm (AAA) with a grid size of 1.5 mm.

Table 1

Dose targets and constraints for treatment planning.
Structure	Metrics	Objective
PTV	V₁₀₀(%)	≥ 95%
PTV	PIDL(%)	≥ 75%
Bladder	V_37Gy(cc)	< 10 cc
	V₁₀₀(%)	< 10%
	V₅₀(%)	< 50%
Rectum	V_36Gy(cc)	< 1 cc
	V₁₀₀(%)	< 5%
	V₉₀(%)	< 10%
	V₈₀(%)	< 20%
	V₇₅(%)	< 25%
	V₅₀(%)	< 50%
Femoral head	V₄₀(%)	< 5%
Urethra	V_37Gy(%)	< 50%
Penile bulk	V_29.5Gy(%)	< 50%
V_xx, percentage of PTV or OAR volume receiving at least xx% dose of 36.25 Gy; PIDL, Prescription isodose line; V_xxGy, volume of PTV or OAR receiving at least xxGy.

2.2 Treatment efficiency

The delivery time and the MUs of two kinds of techniques were recorded to estimate the delivery efficiency. The delivery time includes beam-on time and operation interval.

2.3 Dosimetric evaluation

2.3.1 Common dose metrics

As is listed in Table 2, the maximum, minimum and mean dose (D_max, D_min and D_mean) as well as coverage (V₁₀₀) of CTV and PTV were evaluated.. Meanwhile V₁₂₀, V₁₂₅ and V₁₃₀ of PTV were also recorded to compare the details of hot spots in target volume. The volumes covered by 37 Gy, 100% and 50% of prescription isodose line (PIDL) for bladder, and that covered by 36 Gy, 100%, 90%, 80%, 75%, 50% of PIDL for rectum were categorized for plan evaluation. Meanwhile, D_max and D_mean were analyzed for all the OARs. To investigate the details of dose distribution outside PTV, V₂₀,V₅₀ and V₁₀₀ of normal tissue were also compared.

Table 2

Comparison of dose-volume parameters and integral doses of target and OARs.
	EDGE ± SD	CK ± SD	p
CTV
D_max (Gy)	47.64 ± 0.40	46.57 ± 0.32	< 0.01
D_min (Gy)	35.31 ± 0.80	32.84 ± 2.23	< 0.01
D_mean (Gy)	42.07 ± 1.26	43.23 ± 0.45	< 0.01
V₁₀₀	99.75 ± 0.36	99.50 ± 0.60	0.34
ID (Gy·cc)	2410.33 + 649.46	2483.49 + 682.37	0.02
PTV
D_max (Gy)	47.64 ± 0.40	46.57 ± 0.32	< 0.01
D_min (Gy)	26.82 ± 1.68	28.36 ± 1.81	0.12
D_mean (Gy)	40.77 ± 0.75	41.71 ± 0.46	< 0.01
V₁₀₀(%)	95.00 ± 0.00	95.35 ± 0.53	0.07
V₁₂₀(%)	24.45 + 10.02	41.04 + 12.22	< 0.01
V₁₂₅(%)	7.91 + 5.94	4.97 + 4.21	0.11
V₁₃₀(%)	0.32 + 0.03	0.00 + 0.00	< 0.01
ID (Gy·cc)	3928.84 + 871.05	4041.52 + 914.32	< 0.01
Bladder
D_max (Gy)	39.51 ± 3.51	42.34 ± 1.28	0.02
D_mean (Gy)	11.00 ± 3.23	18.95 ± 4.64	< 0.01
V_{37G y} (cc)	1.09 ± 1.97	3.74 ± 2.07	0.01
V₁₀₀(%)	0.92 ± 1.33	3.55 ± 2.27	0.01
V₅₀(%)	19.95 ± 6.71	45.22 ± 18.72	< 0.01
ID (Gy·cc)	1720.11 + 913.09	3037.32 + 1873.76	< 0.01
Rectum
D_max (Gy)	35.61 ± 1.28	38.94 ± 0.91	< 0.01
D_mean (Gy)	13.14 ± 1.35	14.43 ± 2.14	0.06
V_36Gy (cc)	0.07 ± 0.18	0.73 ± 0.33	< 0.01
V₁₀₀(%)	0.01 ± 0.12	0.79 ± 0.45	< 0.01
V₉₀(%)	0.91 ± 0.89	4.39 ± 1.60	< 0.01
V₈₀(%)	4.57 ± 1.62	9.47 ± 2.89	< 0.01
V₇₅(%)	7.08 ± 1.96	11.40 ± 3.41	< 0.01
V₅₀(%)	29.95 ± 3.82	30.48 ± 8.04	0.86
ID (Gy·cc)	958.67 + 286.66	1086.39 + 367.92	0.02
LFH
D_max (Gy)	14.80 + 2.10	13.63 + 1.15	0.12
D_mean (Gy)	7.83 + 1.34	8.47 + 1.30	0.19
ID (Gy·cc)	568.43 + 156.16	604.17 + 136.18	0.25
RFH
D_max (Gy)	14.43 + 2.51	13.30 + 1.13	0.19
D_mean (Gy)	7.84 + 1.36	8.44 + 1.07	0.50
ID (Gy·cc)	577.59 + 149.27	605.45 + 104.07	0.38
Urethra
D_max (Gy)	24.91 + 11.90	34.75 + 6.67	< 0.01
D_mean (Gy)	4.09 + 2.04	14.97 + 2.13	< 0.01
ID (Gy·cc)	152.82 + 246.74	410.03 + 406.72	< 0.01
Penile bulk
D_max (Gy)	9.34 + 11.82	23.17 + 10.02	< 0.01
D_mean (Gy)	5.29 + 7.24	13.96 + 9.49	< 0.01
ID (Gy·cc)	17.85 + 32.88	38.92 + 42.16	< 0.01
Normal tissue
V₂₀ (cc)	1888.97 + 351.67	2749.98 + 714.67	0.02
V₅₀(cc)	280.83 + 51.54	331.44 + 71.43	0.13
V₁₀₀(cc)	6.87 + 1.31	23.64 + 6.16	< 0.01
ID (Gy·cc)	41384.29 + 6323.47	60572.53 + 9831.61	< 0.01

2.3.2 Integral dose

The Integral dose (ID) of radiation delivered to each volume was defined as follows according to reference[24]: (see Equation 1 in the Supplementary Files)

where is the mean dose delivered to volume V[cc] (where cc—cubic centimeter). v_i is the volume of voxels receiving dose d_i. ID formula was employed to calculate and compare the absorbed dose in target, OARs and the normal tissue, for both irradiation techniques. Since the dose distribution in each volume is heterogeneous,ID were calculated based on differential DVH.

2.3.3 CI, HI and GI

Additionally, conformity index (CI), new conformity index (nCI), homogeneity index (HI) and gradient index (GI) were also used to quantify the plan quality. The conformity index (CI) and new conformity index (nCI) describes how well the dose conforms to the boundary of the target volume and was defined as follows [25, 26] : (see Equations 2 and 3 in the Supplementary Files)

where V^Rx is the prescription isodose volume while V_PTV and are the volume of PTV and that covered by the PIDL. Smaller CI and nCI imply a more conformal plan and the ideal values for both indices are 1.0.

The homogeneity index (HI) evaluates the degree of uniformity of dose inside the target volume [27]. Mathematically, the index was calculated according to the following equation: (see Equation 4 in the Supplementary Files)

where D₂ (D₉₈) is the dose that covers 2% (98%) of the PTV, and D_P is prescription dose. Usually, HI > 0, and HI = 0 means each voxel of target volume receives the same dose.

The gradient index (GI) is implemented to assess the degree of the dose fall-off outside the target [28]. This index was expressed as follows: (see Equation 5 in the Supplementary Files)

where V₅₀ and V₁₀₀ are the volumes covered by 50% and 100% prescription dose, respectively. A smaller value of GI indicates steeper dose fall-off.

2.4 Radiobiological evaluation

2.4.1 EUD

The equivalent uniform dose (EUD), obtained with the DVH reduction method, is used to convert the inhomogeneous dose distribution into a simple uniform dose [29, 30]. The EUD calculation was based on the phenomenological model suggested by Niemierko [29] and was defined as: (see Equation 6 in the Supplementary Files)

where v_i is the percentage of voxels receiving dose d_i. The v_i and d_i values are acquired from the DVHs and the sum of v_i over all voxels equals to 1. a is a parameter which reflects the dose response property of distinct organs, and in some literatures the parameter n is used with a = 1/n. In clinical practice, a large negative value is employed to tumor, while large positive and small positive values are used for serial and parallel organs, respectively. a or n values in Table 3 were used here for tumor[30], bladder[31], rectum[32], femoral head[28, 29], urethra[33] and penile bulk[34]. DVH of different doses per fraction is converted into biologically equivalent physical dose of 2 Gy per fraction (EQD₂) using the linear quadratic (LQ) model according to reference [29]. In the formula of EQD₂, n_f is the number of fractions. The α/β is a parameter from the issue-specific LQ model of the certain organ, determining the fractionation sensitivity. α/β values in Table 3 were used here for tumor[10–12], bladder[35], rectum[36], femoral head[37]. Since there was no clinical data of α/β values for urethra and penile bulk, α/β = 3.0 was applied here as was usually used for most of OARs,

Table 3

EUD, TCP and NTCP model parameters.
	α/β(Gy)	a	γ₅₀	TCD50(Gy)	Endpoint
Tumor	1.5	-10	1.4	57.3	5-year ASTRO free from recurrence
	α/β(Gy)	n	m	TD50(Gy)
Bladder	7.5	0.06	0.195	72.5	RTOG grade 2 acute genitourinary
Rectum	5.4	0.09	0.13	76.9	Grade ≥ 2 late rectal toxicity
LFH	6.0	0.25	0.12	65	Necrosis
RFH	6.0	0.25	0.12	65	Necrosis
Urethra	3.0	0.3	0.37	70.7	clinical stricture/perforation
Penile bulk	3.0	0.74	0.86	70.1	erectile dysfunction ≥ 1

2.4.2 TCP

EUD based tumor control probability (TCP) proposed by Niemierko can be expressed with logistic equation [38]: (see Equation 8 in the Supplementary Files)

where TCD₅₀ is the dose for achieving a 50% probability of tumor control as the tumor is irradiated homogeneously, and γ₅₀ is the slope of sigmoidal dose response curve of tumor. TCD₅₀ = 57.3 Gy and γ₅₀=1.4 were used here with the endpoint of 5-year ASTRO free from recurrence according to reference[39].

2.4.3 NTCP

The normal tissue complication probability (NTCP) were calculated based on the Lyman-Kutcher-Burman (LKB) model[29, 30], in which NTCP for an organ to equivalent uniform dose (EUD) is given by (see Equation 9 in the Supplementary Files)

where (see Equation 10 in the Supplementary Files)

m is a dimensionless parameter and TD₅₀ is the whole organ dose for which NTCP is 50%. TD₅₀ and m for bladder[31], rectum[32], femoral head[29, 30], urethra[33] and penile bulk[34] with definitive clinical endpoints were listed in Table 3.

2.5 Statistical analysis

All the parameters were calculated from the DVHs with an in-house program based on C++. Statistical analyses were carried out using IBM SPSS Statistics version 21 (SPSS Inc.Armonk, NY). A paired t-test was performed to analyze the difference between EDGE and CK plans, and a p value < 0.05 was considered to reveal statistical significance.

3.1 Dose-volume metrics

All planning constraints detailed in Table 1 were met by both EDGE and CK plans. The comparison of isodose lines from 20–120% of the prescription dose for a selected case is illustrated in Fig. 1. Obviously, both plans are very conformal and provide adequate coverage of PTVs. Besides, we can find that the 100% PIDL (with red color) of EDGE plan is closer to PTV boundary than that of CK plan.

The averaged DVHs of CTV, PTV, bladder, rectum, left and right femoral heads, urethral as well as penile bulk are displayed in Fig. 2(a)-(h), respectively. The values of dose-volume parameters of target and OARs are detailed in Table 2. From both Fig. 2(a)-(h) and Table 2, CTV and PTV coverage of EDGE and the CK plans were found to be of similar levels and showed no obvious difference. The mean dose (D_mean) of CTV and PTV are higher for CK, indicating larger ablation effect within target.

The bladder DVH indices (D_max, D_mean, V_37Gy, V_100% and V_50%) from the EDGE plans were also statistically lower than the CK plans, presenting a distinct reduction of irradiation. The EDGE plans achieved slightly better rectum protection with respect to D_max, V_36Gy, V_100%, V_90%, V_80% and V_75%. The irradiation dose of right and left femoral heads for both systems were very low and showed no significant difference in terms of D_max and D_mean. Moreover, D_max and D_mean of urethra and penile bulk were much lower for EDGE plans. The volumes normal tissue covered by 20%, 50% and 100% PIDL were all lower for EDGE plans, which were associated with better conformity and steeper dose fall-off gradient. Meanwhile, the integral dose of target volumes were a little larger for CK plans. Otherwise, the ID of OARs were much lower for bladder, urethral, penile bulk as well as normal tissure outside PTV for EDGE plans, while there were no much significant difference of ID for rectums and femoral heads.

3.2 Dosimetric indexes and delivery efficiency

The average of dosimetric indexes including CI, nCI, HI and GI are listed in Table 4. It was apparent that EDGE plans are more conformal with CI (nCI) value of 1.07 ± 0.03 (1.13 ± 0.03) compared to that of the CK plans with 1.20 ± 0.03 (1.25 ± 0.04), which was consistent as shown in Fig. 1. The higher average HI value of 0.26 ± 0.03 for the EDGE plans compared to that of CK with 0.24 ± 0.03 (Table 4) means the hot point is smaller in CK plans than that in EDGE. A slightly steeper GI was achieved in EDGE plans but there was no significant difference. In addition, the delivery efficiencies were quantified in terms of monitor units (MUs) and delivery time. It indicated that the average MUs and delivery time were reduced by 72% and 91% using EDGE compared to CK. This means less additional irradiation and higher treatment efficiency by utilizing EDGE.

Table 4

Average values of CI, nCI, HI and GI, MUs and delivery time per fraction between the EDGE and the CyberKnife plans.
	EDGE ± SD	CK ± SD	p
CI	1.07 ± 0.03	1.20 ± 0.03	< 0.01
nCI	1.13 ± 0.03	1.25 ± 0.04	< 0.01
HI	0.26 ± 0.03	0.24 ± 0.03	0.09
GI	3.70 ± 0.30	3.87 ± 0.21	0.09
MUs	2602.07 ± 330.41	9419.55 ± 1619.01	< 0.01
Delivery time(min)	4.10 ± 0.09	46.35 ± 3.87	< 0.01

3.3 Radiobiological comparison

The radiobiological parameter EUD extracted from DVHs for CTV, bladder, rectum, left and right femoral heads, urethral and penile bulk, as well as TCP of CTV and NTCP of all these OARs were compared between the EDGE and the CK plans. The average values, standard deviation (SD), and p values were detailed in Table 5. The CK plans provided a slightly greater EUD and comparatively higher TCP than the EDGE plans. However, the larger EUD for bladder, rectum, urethral and penile bulk in CK plans were obtained, which indicated dramatically increasing NTCP of CK compared to EDGE plans for the four organs, respectively. The NTCP of femoral heads were too small to be considered, and showed no significant difference.

Table 5

Comparison of radiobiological parameters (EUD, TCP and NTCP) between the EDGE and the CK plans.
	EUD (Gy)			TCP/NTCP (%)
	EDGE ± SD	CK ± SD	p	EDGE ± SD	CK ± SD	p
CTV	113.04 ± 6.83	119.81 ± 2.99	0.02	97.69 ± 0.82	98.40 ± 0.22	0.03
Bladder	38.79 ± 5.15	46.47 ± 3.85	< 0.01	0.29 ± 0.18	1.93 ± 1.30	< 0.01
Rectum	38.01 ± 2.21	44.76 ± 1.91	< 0.01	3.93 ± 0.84	7.27 ± 1.29	< 0.01
LFH	9.23 ± 1.05	9.01 ± 1.38	0.71	< 0.0001	< 0.0001	0.94
RFH	9.16 ± 1.21	8.94 ± 1.10	0.72	< 0.0001	< 0.0001	0.96
Urethra	12.03 ± 5.80	24.99 ± 4.60	< 0.01	1.41 ± 0.93	4.24 ± 1.54	< 0.01
Penile bulk	7.41 ± 14.83	20.84 ± 20.67	< 0.01	15.55 ± 7.26	21.76 ± 11.18	< 0.01
SD: standard deviation; EUD: equivalent uniform dose; TCP: tumor control probability: NTCP: normal tissue complication probability.

In this study, we compared the plan quality of EDGE and CK in terms of dosimetric properties, delivery efficiency and predicted biological outcomes for prostate SBRT treatment. Both of the two techniques were able to produce clinically acceptable plans with adequate target irradiation and normal tissue sparing. Despite both systems were able to achieve excellent dose distribution according to the results above, EDGE had a little better performance in dosimetric results of conformity of PTV and better OAR sparing.

The EDGE plans were optimized using high definition HD120 MLCs (with minimum spatial resolution of 2.5 mm) on the X axis with even littler size of gap on the Y axis, while the CK plans were made by 1–2 circular cones with size of 20∼30 mm. The high resolution of MLCs make it easier to reach more conformal dose distribution of PTV for EDGE, which will largely reduce the number of sub-fields.

The main reasons for the normal tissue sparing differences were due to the different characteristics of the two systems, which could be explained in two aspects. First and foremost, the plan optimization processes of the Multiplan version 4.0.2 and Eclipse 13.5 are very different. In the Multiplan, we could only set the maximum doses of OARs as constraints and optimize the mean doses of OARs, while in the Eclipse, several constraints could be set on the DVH curves of each OAR. This is one of the major reasons for superior OARs sparing of EDGE system. Further improvement for CK plan is feasible, if the optimization algorithm of Multiplan® evolves. Secondly, the beam arrangements in the process of planning optimization may play important roles for the dose distribution. CK offers superiority of highly flexible angles, which delivered noncoplanar beams from all directions moved by the robotic arm while EDGE rarely used noncoplanar beams in the region of abdomen due to mechanical and geometrical limitations. However, the CK did not benefit from this advantage in this study because the beams of CK were mainly distributed in directions perpendicular to cranio-caudal (CC) direction in these plans, as the final results of beam-angle optimization in light of the anatomical position of the prostates. The most beneficial beam angles were similar to those from two full 360 rotation arcs (178 segments for each plan) of EDGE which were rotated around CC direction.

As noted above, EDGE had the shortened average delivery time and the fewer MUs largely, as displayed in Table 4. Lessening treatment time means less scatter dose, which may lower the probability of secondary malignancies. On the other hand, decreased delivery time of EDGE can potentially reduce the effects of intra-fractional motion, and make the patients more comfortable. The VMAT technique, which delivers from a large number of angles with fewer control points, has been showed to decrease the number of MUs significantly, along with even lower MUs for dual-arc VMAT plans under the same condition as reported by Quan et al [40]. Moreover, EDGE system has 10FFF mode delivering the maximum high dose rate of 2400 MU per minute which severely shortens the beam-on time [18, 23].

The radiobiological parameters in terms of EUD and TCP (NTCP) were calculated from DVHs, as showed in Table 5. The results indicated that the EDGE plans have slightly reduced CTV EUD than the CK plans, the results of which were in agreement with these of dosimetric evaluation. The mean EUD were lower for the OARs such as bladder, rectum, urethral and penile bulk in the EDGE plans in accordance with the calculated lower NTCP values consequentially. Both groups of plans were able to maintain high EUD to the tumors and yield good tumor TCP while low NTCP of normal structures were obtained in relation to late toxicity effects. For predicted clinical benefits, this two treatment modalities can be considered to be safe.

Additionally, there also exists a concern for tumor and adjacent organs position variations throughout the course of treatment after the online match per fraction[41–43]. The intra-fraction prostate displacements were reported to be > 3 mm and > 5 mm were 24% and 5% of fractions respectively [43]. In this case, the target localization and real-time tracking systems are necessary to improve confidence in radiation dosimetry. Previous studies showed that CK has the competitive in light of target localization to deliver accurately in comparing conventional linear accelerator [44]. For the CK, two kilovoltage x-ray generators and two hereafter cameras are incorporated to finish fiducial tracking for prostate motion [45]. Very small set-up errors were observed with 1.8 mm in the anterior posterior direction and 1.4 mm in the superior inferior direction [46]. However, EDGE system, designed for SBRT or SRS, has been improved to integrate Calypso 4D system capable of monitoring target position on the basis of radiographic transponder locations. Calypso system was reported to present a treatment accuracy of average 3D difference of 1.5 mm in dose delivery [47]. Thus EDGE has similar performance against motion uncertainties. For this reason, we delineated target margins for EDGE system according to the same protocols used for the CK. For all that, EDGE is lack of practical experience clinically by Calypso 4D system compared to CK.

Several limitations should be recognized in this investigation. Firstly, because the representative version of CyberKnife G4 system with the fixed cone is most commonly used, it was selected to compare to the latest EDGE system in our study. The latest generation of CK system M6™, with IRIS collimator and InCise MLC, may increase the output rate and conformal dose distribution as well as to reduce delivery time. Otherwise, the radiobiological parameters presented in this study are highly dependent on the model and related parameters. Therefore, the radiobiological responses could only be regarded as references when making clinical decisions. Further studies on clinical trials are required to collect practical experience and find out which is the valuable option for localized prostate cancer.

A comparative quantitative assessment of the dosimetric and radiobiological indices of plans for both CybkerKnife and EDGE systems was made in this study. We confirm that radiotherapy systems with different characteristics should be investigated and utilized to help radiation oncologists choose a proper SBRT method for each individual patient to get better therapeutic effects. EDGE system can be used as an option for prostate cancer, especially for patients who cannot remain lying in bed for a long time.

SBRT: stereotactic body radiation therapy; PTV: planning tumor volume; CI: conformity index; nCI: new conformity index; HI: homogeneity index; GI: gradient index; ID: integral dose; EUD: equivalent uniform dose; TCP: tumor control probability; NTCP: normal tissue complication; MUs: monitor units; SABR: Stereotactic Ablative Radiotherapy; OAR: organ at risk; NCCN: National Comprehensive Cancer Network; MLC: multileaf collimator; FF: Flattening Filter; FFF: Flattening Filter Free; DVH: dose volume histogram; CT: computed tomography; MR: magnetic resonance; AAA: analytical anisotropic algorithm; PIDL: prescription isodose line; LQ model: Linear Quadratic model; SD: standard deviation.

Ethics approval and consent to participate

The study was approved by the institutional review board of our hospital.

Consent for publication

The consents for publication of data have been obtained from patients.

Availability of data and materials

Not applicable.

Competing interests

The authors state that they have no competing interests.

Funding

This study was sponsored by Chinese Postdoctor Foundation(2018M632904), and National Natural Science Foundation of China (Grant No. 81871509 and 81872453).

Authors’ contributions

Zhitao Dai: participation in the whole work; perception and design; generating CK plans; drafting of the article; data analysis;final approval of the version to be published.

Lian Zhu: re-generating the EDGE plans and drafting the manuscript.

Tingting Cao: data analysis;drafting of the article.

Aihua Wang: re-generating the EDGE plans.

Xueling Guo: generating CK plans;data analysis.

Yongming Liu: generating CK plans.

Yayun Zhuang:re-generating the EDGE plans.

Peiying Yang:executing plan on EDGE system.

Ning Li: drafting and final approval of the version to be published.

Huojun Zhang: perception and final approval of the version to be published.

Zuoling Xiang: final approval of the version to be published.

Acknowledgements

No acknowledgement.

Freeman DE, and King CR. 2011. Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes. Radiat Oncol . 6:3.
Katz AJ, Santoro M, Ashley R, Diblasio F, Witten M.. 2010. Stereotactic body radiotherapy for organ-confined prostate cancer. BMC Urlogy. 10:1.
King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, and Presti JC Jr. 2009. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int J Radiat Oncol Biol Phys. 73:1043-8.
Madsen BL, Hsi RA, Pham HT, Fowler JF, Esagui L, and Corman J. 2007. Stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP), 33.5 Gy in five fractions for localized disease: first clinical trial results. Int J Radiat Oncol Biol Phys. 67:1099-105.
Mohler JL, Armstrong AJ, Bahnson RR, et al. 2012. Prostate Cancer, Version 1.2016. J Natl Compr Canc Netw 2016; 14:19-30.
Sudahar H, Kurup PG, Murali V, et al. 2012. Equivalent normalized total dose estimates in cyberknife radiotherapy dose delivery in prostate cancer hypofractionation regimens. J Med Phys. 37(2):90-6.
Henderson DR, Tree AC, and van As NJ. 2015. Stereotactic body radiotherapy for prostate cancer. Clinical oncology. 27:270-9.
Miralbell R, Roberts SA, Zubizarreta E, and Hendry JH. 2012. Dose-fractionation sensitivity of prostate cancer deduced from radiotherapy outcomes of 5,969 patients in seven international institutional datasets: α/β= 1:4(0:9−2:2) Gy. Int J Radiat Oncol Biol Phys. 82(1):e17-24.
Ritter M, Forman J, Kupelian P, Lawton C, and Petereit D. 2009. Hypofractionation for prostate cancer. Cancer J. 15(1):1-6.
Brenner DJ, and Hall EJ. 1999. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat oncol Biol Phys. 43: 1095-101.
Dasu A, and Toma-Dasu I. 2012. Prostate alpha/beta revisited—an analysis of clinical results from 14 patients. Acta Oncologica . 51(8):963-974.
Cheung R, Tucker SL, Lee AK, et al. 2005. Dose-response characteristics of low- and intermediate-risk prostate cancer treated with external beam radiotherapy. Int J Radiat Oncol Biol Phys. 61(4):993-1002.
Alongi F, Cozzi L, Arcangeli S, et al. 2013. Linac based SBRT for prostate cancer in 5 fractions with VMAT and flattening filter free beams: preliminary report of a phase II study. Radiat Oncol. 8:171.
Antypas C, and Pantelis E. 2008. Performance evaluation of a CyberKnife G4 image-guided robotic stereotactic radiosurgery system. Phys Med Biol. 53(17):4697-718.
King CR, Brooks JD, Gill H, and Presti JC Jr. 2012. Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys. 82(2):877-82.
Hossain S, Xia P, Huang K, Descovich M, et al. 2010. Dose gradient near target-normal structure interface for nonisocentric CyberKnife and isocentric intensity-modulated body radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys. 78(1):58-63.
Wen N, Li H, Song K, Chin-Snyder K, et al. 2015. Characteristics of a novel treatment system for linear accelerator-based stereotactic radiosurgery. J Appl Clin Med Phys. 16 (4):125-48.
Lang S, Shrestha B, Graydon S, et al. 2013. Clinical application of flattening filter free beams for extracranial stereotactic radiotherapy. Radiother Oncol. 106 (2):255-9.
MacDougall ND, Dean C, Muirhead R. 2014. Stereotactic Body Radiotherapy in Prostate Cancer: Is Rapidarc a Better Solution than Cyberknife? Clinical Oncology. 26:4-9.
Lin YW, Lin KH, Ho HW, et al. 2014. Treatment plan comparison between stereotactic body radiation therapy techniques for prostate cancer: Non-isocentric CyberKnife versus isocentric RapidArc. Physica Medica. 30:654-61.
Ceylan C, Kucuk N, Bas Ayata H, et al. 2010. Dosimetric and physical comparison of IMRT and CyberKnife plans in the treatment of localized prostate cancer. Rep Pract Oncol Radiother. 15(6):181-9.
Lukka H, Bahary J P, Lawton C, et al. 2015. RTOG 0938: a randomized phase II trial of hypofractionated radiotherapy for favorable risk prostate cancer. RTOG, Hamilton, Canada.
Zwahlen DR, Lang S, Hrbacek J, et al. 2012. The use of photon beams of a flattening filter-free linear accelerator for hypofractionated volumetric modulated arc therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys. 83(5):1655-60.
Aoyama H, Westerly D, Mackie T, et al. 2006. Integral radiation dose to normal structures with conformal external beam radiation. Int J Radiat Oncol Biol Phys. 64:962-7.
van’t Riet A, Mak AC, Moerland MA, et al. 1997. A conformation number to quantify the degree of conformality in brachytherapy and external beam irradiation: application to the prostate. Int J Radiat Oncol Biol Phys. 37(3): 731-6.
Feuvret L, Noël G, Mazeron JJ, and Bey P. 2006. Conformity index: a review. Int J Radiat Oncol Biol Phys. 64(2):333-42.
Wu Q1, Mohan R, Morris M, et al. 2003. Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced head-and-neck squamous cell carcinomas. I: dosimetric results. Int J Radiat Oncol Biol Phys. 56(2): 573-585.
Paddick I, and Lippitz B. 2006. A simple dose gradient measurement tool to complement the conformity index. J Neurosurg. 105 Suppl:194-201.
Niemierko A. 1997. Reporting and analyzing dose distributions: a concept of equivalent uniform dose. Med Phys. 24(1):103-10.
Luxton G, Keall PJ, and King CR. 2008. A new formula for normal tissue complication probability (NTCP) as a function of equivalent uniform dose (EUD). Phys Med Biol. 53:23.
Boulé TP, Gallardo Fuentes MI, Roselló JV, Et al. 2009. Clinical comparative study of dose-volume and equivalent uniform dose based predictions in post radiotherapy acute complications. Acta Oncol. 48(7):1044-53.
Michalski JM, Gay H, Jackson A, et al. 2010. Radiation dose-volume effects in radiation-induced rectal injury. Int J Radiat Oncol Biol Phys. 76(Suppl 3):S123-9.
Panettieri V, Rancati T, Onjukka E, et al. 2018. PV-0321: Influence of urethra contouring on NTCP models predicting urethral strictures in prostate HDRB. Radiother Oncol. 127(Suppl 1): S170.
Coates J, Jeyaseelan A K, Ybarra N, et al. 2015. Contrasting analytical and data-driven frameworks for radiogenomic modeling of normal tissue toxicities in prostate cancer. Radiother Oncol. 115(1):107-113.
Thames HD, and Hendry JH. 1987. Fractionation in radiotherapy. London-New York-Philadelphia: Taylor & Francis.
Brenner DJ. 2004. Fractionation and late rectal toxicity. Int J Radiat Oncol Biol Phys. 60(4):1013-5.
Takam R, Bezak E, Yeoh EE, Marcu L. 2010. Assessment of normal tissue complications following prostate cancer irradiation: comparison of radiation treatment modalities using NTCP models. Med Phys. 37(9):5126-37.
Niemierko A. 1999. A unified model of tissue response to radiation. In: Proceedings of the 41th AAPM annual meeting; 1999. Nashville, Tennessee: Med Phys. p. 1100.
Okunieff P, Morgan D, Niemierko A, Suit HD. 1995. Radiation Dose-response of human tumors. Int J Radiat Oncol Biol Phys. 32(4): 1227-37.
Quan EM, Li X, Li Y, et al. A comprehensive comparison of IMRT and VMAT plan quality for prostate cancer treatment. Int J Radiat Oncol Biol Phys. 83(4):1169-78.
Langen KM, and Jones DT. Organ motion and its management. Int J Radiat Oncol Biol Phys. 50(1):265-78.
Rosewall T, Chung P, Bayley A, et al. 2008. A randomized comparison of interfraction and intrafraction prostate motion with and without abdominal compression. Radiother Oncol. 88(1):88-94.
Reggiori G, Mancosu P, Tozzi A, et al. 2010. Cone beam CT pre- and post-daily treatment for assessing geometrical and dosimetric intrafraction variability during radiotherapy of prostate cancer. J Appl Clin Med Phys. 12(1):3371.
Zhao B, Yang Y, Ozhasoglu C, et al. Comparison of RapidArc‐Based Radiosurgery with Cone‐Based Cyberknife Treatment for Multiple Intracranial Tumors. Medical Physics. 39(6Part20):3852
Murphy MJ. An automatic six-degree-of-freedom image registration algorithm for image-guided frameless stereotaxic radiosurgery. Med Phys. 24(6):857-66.
Alasti H, Petric MP, Catton CN, and Warde PR. 2001. Portal imaging for evaluation of daily on-line setup errors and off-line organ motion during conformal irradiation of carcinoma of the prostate. Int J Radiat Oncol Biol Phys. 49(3):869-84.
Willoughby TR, Kupelian PA, Pouliot J, et al. 2006. Target localization and real-time tracking using the Calypso 4D localization system in patients with localized prostate cancer. Int J Radiat Oncol Biol Phys. 65(2):528-34.

Equations.pdf

Download PDF

Version 1

posted

You are reading this latest preprint version

Dosimetric and biological comparison of treatment plans between EDGE and CyberKnife systems in stereotactic body radiation therapy for localized prostate cancer

Status:

Version 1

Abstract

Figures

1. Introduction

2. Materials And Methods

3. Results

4. Discussion

5. Conclusion

List of Abbreviations

Declarations

References

Supplementary Files

Status:

Version 1