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Dosimetric comparison among cyberknife, helical tomotherapy and VMAT for hypofractionated treatment in localized prostate cancer

Abstract Hypofractionation for localized prostate cancer treatment is rapidly spreading in the medical community and it is supported by radiobiological evidences (lower α/β ratio compared with surrounding tissues). Stereotactic body radiation therapy (SBRT) is a technique to administer high doses with great precision, which is commonly performed with CyberKnife (CK) in prostate cancer treatment. Since the CyberKnife (CK) is not available at all radiotherapy center, alternative SBRT techniques are available such as Volumetric Modulated Arc Therapy (VMAT) and Helical Tomotherapy (HT). The aim of the present study was to compare the dosimetric differences between the CK, VMAT, and HT plans for localized prostate cancer treatment. Seventeenpatients have been recruited and replanned using VMAT and HT to this purpose: they received the treatment using the CK with a prescription of 36.25 Gy in 5 fractions; bladder, rectum and penis bulb were considered as organs at risk (OAR). In order to compare the techniques, we considered DVHs, PTV coverage, Conformity Index and new Conformity Index, Homogeneity Index, beam-on time and OARs received dose. The 3 treatments methods showed a comparable coverage of the lesion (PTV 95%: 99.8 ± 0.4% CK; 98.5 ± 0.8% VMAT; 99.4 ± 0.5% HT. P < .05) and good sparing of OARs. Nevertheless, the beam-on time showed a significant difference (37 ± 9 m CK; 7.1 ± 0.3 m VMAT; 17 ± 2 m HT. P < .05). Our results showed that, although CK is the best SBRT technique for prostate cancer treatment, in case this technology is not available, it can be replaced by a similar treatment delivered by VMAT technique. VMAT can be administrated only if it has an appropriate Image Guided Radiation Therapy (IGRT) tracking system.


Introduction
Prostate cancer is the second tumor most commonly diagnosed among men around the world. [1] The risk of developing prostate cancer is closely related to aging: about 14% at 50 years old and 50% from 80 years old upward. [2] Indeed, about 1 million men are diagnosed with prostate cancer each year and this number is expected to increase due to general improvement in living conditions and therefore the world population aging. [3] Nowadays is possible to detect such malignancy in its early stages and intervene promptly, by allowing low mortality rate, thanks to screening campaigns, early diagnoses and technological progress.
Exclusive radiotherapy (RT) administered in localized prostate cancer, as an alternative to radical prostatectomy, offers comparable results in terms of overall survival and Quality of Life (QoL), to those ones of surgery. [4] Its use is approximately 25% in patients <65 years old and 40% in patients over 65 years old. [5] In external beam radiotherapy (EBRT) the standard fractionation is 1.8-2 Gy/fraction, but according to radiobiology knowledge and according to the linear-quadratic model, the a/b ratio differences with healthy tissues surrounding the tumor can dramatically affect the fractionation, Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP). The linear quadratic model describes the survival probability of a cell (SF) following dose radiation exposure (d) as SF = exp[-ad-bd 2 ], where a and b are parameters describing the cells radiosensitivity. Each tissue has a a/b ratio which has units of Gy and reflects the response to a radiation dose (the same dose delivered to 2 different tissues can generate different effects). Moreover, computational models of TCP show how the tumor control varies according to dose/fraction (fx). In particular if the a/b ratio of the tumor is lower than the surrounding healthy tissues, the high dose/fraction (greater than 2 Gy/fx) increases the tumor control probability. On other hand if the a/b ratio of the tumor is higher than the surrounding tissues the standard fractionation (2 Gy/fx) is preferred. Several studies establish that the a/b ratio for prostate cancer is 1.5 Gy, lower than the nearby organs (rectum, bladder), which allowed the physicians to move towards hypofractionated regimes and dose escalation. [6][7][8][9][10][11][12] The hypofractionation has significant advantages in terms of radiobiological effects, outcomes improvement, treatment curse reduction with costs decrease, improvement of patient QoL and compliance to treatment. Thanks to these advantages, the medical community is moving in this direction for prostate cancer treatment and other tumors if radiobiological evaluations consent hypofractionation. [13] Technological advances in imaging, treatment-planning, dose delivery and dose verification, combined with the results of moderately hypofractionated randomized trials, [14][15][16][17][18][19] allow higher fraction doses in a low number of fractions (ablative hypofractionation) as in Stereotactic body radiotherapy (SBRT). [20][21][22][23][24] In SBRT of prostate cancer, dose delivery and target tracking accuracy are important to increase treatment efficacy and decrease side effects, since the prostate is subject to organ motion. There are different SBRT techniques for prostate cancer treatment: nonisocentric techniques that employing robotic arm-based linear accelerators (LINACs) as CyberKnife System (CK, Accuray, Sunnyvale, CA, USA), and helical or volumetric isocentric coplanar techniques with gantry rotation around the body patient such as VMAT and helical tomotherapy (HT Accuray, Sunnyvale, CA, USA). The CyberKnife System is the most common SBRT modality used in localized prostate cancer treatment. CK is 6 MV photon beam linear accelerator installed on a 6 degrees of freedom robotic arm. A wide range of movement allows high conformity by following irregular edges of the lesion and avoids the OARs due to the different entry points of the treatment fields. It is an IGRT where the image system (2 orthogonal kilovoltage X-ray imagers) allows the linear accelerator to follow the lesion, by tracking of golden intraprostatic fiducials markers, and it consents to adapt beams delivery and correct the patient position. The helical tomotherapy is an IMRT (Intensity Modulated Radiation Therapy) coplanar arc with binary multileaf collimator (MLC) and mega-voltage computer tomography (MVCT). Table movement and at the same time a rotating beam around the patient, generate the helical geometry of the treatment. In the VMAT technique, delivered by a LINAC, during the gantry rotation around the isocenter, the field is continuously shaped by a MLC and also the dose rate is modulated, in order to avoid or reduce the delivered dose to the OARs.
In this study, we aim to compare the dosimetric results of CK treatment plans with HT ones and with VMAT ones, for the tumor target and the OARs by delivering 36.25 Gy in 5 fractions (7.25 Gy per fraction).

Patients and treatment planning
In this study have been involved 17 patients with a localized prostate cancer. They have been treated in the "Instituto Nazionale Tumori -IRCCS Fondazione G. Pascale" with SBRT CK system in the period between June 2015 and October 2017. Four gold fiducials markers had been implanted into prostate and 7/10 days after placement, patients underwent a non-contrast simul-CT scan (1 mm cuts) in supine position with personalized immobilization system and thin-cut MRI scans. Target volumes and OARs delineation has been performed by physicians using a simul-CT scan with MRI fusion. Gross target volume (GTV) was defined as prostate gland, Clinical target volume (CTV) was equal to GTV and Planning target volume (PTV) was CTV with a 3 mm expansion posteriorly and 5 mm in all directions. The rectum, bladder and penis bulb were contoured as OARs. The CK treatment planning was performed using the Precision inverse treatment planning system (Accuray Inc., Sunnyvale, CA) and the prescription dose was 36.25 Gy at 80% isodose line delivered in 5 fractions. The prescription dose covered at least 95% of the PTV and the constraints for OARs are presented in Table 1.
In order to compare the dosimetric results among the different techniques, the CT images and contours (PTV and OARs), for all patients, were exported as DICOM-RT files to the planning systems of HT (Hi-Art 4.2.3 System) and VMAT (TPS Philips, Pinnacle v. 16.0.2) and re-planned.
For the HT plans was selected a field width of 2.5 cm, a pitch of 0.145 and a modulation factor of 3.6. Therefore, all patients had 3 radiotherapy plans each.
VMAT treatment plans were computed with Pinnacle TPS and the treatments geometrical setup was decided by experienced medical physicists: 2 arcs of 360°(clockwise/counterclockwise) with a 20°collimator and final gantry spacing 3, in both arches there was a 0°couch kick. VMAT plans were computed for an Elekta Synergy linear accelerator (Elekta, Crowley, UK) equipped with 6 MV photon beam and multileaf collimator with 5 mm leaf.
In both cases the minimum request was that the prescription dose covered at least 95% of the PTV.

Dosimetric and Statistical analysis
In order to achieve dosimetric information for each patient, the best possible treatment was planned by ensuring an optimal PTV coverage and OARs sparing in accordance with the con- Table 1 Constraints for OARs considered in the planification process.

OAR
Dmax Dose limit straints. [20][21][22][23][24][25][26][27] Expert physicians approved resulting plans. After developing all patients plans, DVHs were extracted and analyzed with Matlab (The MathWorks, Inc., Natick, Massachusetts, United States). In Table 2, are presented the dose received by a specified volume percentage of the respective ROI, the homogeneity index (HI), the conformity index (CI), the new conformity index (nCI). Such parameters are evaluated using the following equations: HI is a measure of dose homogeneity inside the tumor volume. HI 95 and HI 98 depend on whether the maximum dose is evaluated as a dose received from 5% (D 5% ) or 2% (D 2% ) of the tumor volume. In case of high homogeneity these parameters will be close to zero.
PIV (Prescription Isodose Volume) is the volume which receives the prescription dose and TIV (Tumor Isodose Volume) is the volume of the tumor which receives the prescribed isodose. The PIV could be not restricted to the tumor volume but could be larger or smaller, ideally a CI value as close as possible to the unit could be desirable. Nevertheless, low CI values can be obtained also in case of missing target, therefore the coverage must be taken into account and hence nCI is defined. For the sake of completeness, CI and nCI were computed only for CK and VMAT since the beam on time for HT was too long for a treatment where no tracking tumor technology is adopted, therefore the HT plans were evaluated not clinically valid and no further analysis were carried out.
PTV Coverage 95% and 98% indicate the volume of PTV receiving the 95% or 98% of the prescribed dose respectively (Table 3). Beam-on time, reported in Table 3, is the time (in minutes) during the beam is turned on and when it deliveries dose. This not consider the needed time to correctly place the patient on the couch based on markers and laser system.
Anova test was used to analyze differences in dosimetric parameters among the 3 planning modalities with a significance level at P < .05 and if only 2 indices were involved in the analysis, a T-test with a significance level at P < .05 was used. The statistical analysis was performed with Matlab. Table 2 summarizes mean values, standard deviations and ranges of the PTV volume, bladder volume, rectum volume and penis bulb volume derived from the contouring operation. We expected a single volume value for every organ. On the contrary, because the 3 used TPS gave slightly different volume values, we considered and illustrated 3 results per instance.

Results
For the sake of clarity, since for each TPS the volume percentages are computed by normalizing them for its own whole recovered volume value these values are reported. In addition, the different constraints values for the OARs obtained with the different techniques (CK, VMAT, HT) and the dose received by 2% (D 2% ) and 5% (D 5% ) of the volume are shown in Table 2.
Such findings are validated by the Figure 1, in which the mean DVHs for PTV, bladder, rectum and penis bulb are shown. The DVHs VMAT curves are always lower than those of CK and HT, and VMAT reaches comparable values to the other ones only at high doses, whereas the CK and HT curves are superimposed or intersect.
The data in Table 2 about the volume of penis bulb that received 29 Gy (V 29 ) deserve a clarification: 29 Gy were reached in only one case with VMAT technique, in 6 cases with CK and 3 cases with HT whereas in the remaining other cases the values were 0%.
The beam on time among the treatment modalities was statistically different: 37 ± 9 m CK vs 7.1 ± 0.3 m VMAT and 17 ± 2 m HT (P < .05).

Discussion
Prostate cancer is a fairly common disease among men in the world. [1][2][3] In recent times, due to scientific progress, several treatment methods became available and in particular hypofractionated radiotherapy is one of the most used.   Moreover, in hypofractionated radiotherapy field various techniques are available, every of them has its pros and cons and not all of them are available in the same medical center. Therefore, in this study dosimetric results about the treatment of the localized prostate cancer by comparing the CK, VMAT, and HT technique are investigated, in order to understand if comparable goals in terms of tumor coverage and OARs sparing can be achieved. [20][21][22][23][24][25][26][27] Trough the comparison between such platforms, there is a general satisfaction about the coverage of the PTV in literature, but conflicting results regarding the OARs sparing could depend on the version of the used TPS, the machines and the expansion margins to create the PTV. [29][30][31][32][33][34] Indeed, in our work the same PTV expansion has been used for each of the 3 techniques, whereas in other cited works authors used larger expansion for HT, VMAT, and IMRT or such parameter is not reported. It is noteworthy that wider margins on one side increase conformity of the used technique but on the other side decrease its sparing capability.
Focusing our attention on the mean DVHs (Fig. 1) and looking at the Table 2, for rectum and bladder the lower doses reached by the VMAT technique and the highest ones by CK are appreciable. However by paying more attention, the maximum sparing is reached at the lowest or intermediate doses whereas comparable values are obtained at high doses. Lower dose is delivered by VMAT to the penis bulb. Even if VMAT allows for the OARs sparing, this does not seem to negatively affect the coverage of tumor volume that is acceptable but the lowest one among the investigated techniques. It is noteworthy that the higher doses reached by CK are expected since this machine is conceived for the SBRT [30,32] and the total dose is prescribed at 80% isodose line. Given this particular feature to dose delivery by CK, it is expected a low dose-homogeneity inside the PTV with respect the other modalities as highlighted by the HI 95 and HI 98 . Moreover, to give a visual interpretation of the numerical indexes exposed above and a better dose delivery understanding to the different technologies, we display, in Figure 2, the dose distribution for the 3 different analyzed modalities. Because of dose delivery during the rotation of the treatment field, VMAT and HT slices show that low doses are delivered all around the PTV. Even though it is possible to observe a more jagged dose structure with CK due to the possibility to exploit multiple corridors and at the same saving www.md-journal.com from low doses healthy tissues. On the other hand, thanks to the technological progress of the abovementioned systems, the 95%, 98% of the prescribed dose is well confined along the PTV edges, and furthermore the dose in CK plans reaches the 110% of the prescribed dose, therefore justifying the lower values for the HI. An important parameter is treatment duration: the longest ones are for the CK (37 minutes) whereas the shortest ones are for VMAT (7.1 minutes). Our beam on time are comparable or faster than those found by Lin et al. [33] The beam on time found for HT is 17 minutes considered not clinically deliverable since there is not a specific tool to track the PTV position during the treatment. Indeed in a such long duration, shifts due to organ motions are expected and therefore the probability to deliver high doses to the OARs and to do not cover the PTV increases. The CK has a longer treatment length as it is equipped with a particular IGRT system to track prostate movement through fiducial markers and KV images acquisition during the whole treatment.
Even if the treatment duration for VMAT is the shortest one compared with other techniques, if an imaging dynamic tracking system is not adopted, it could lead to a missing target or an overtreatment of the PTV and OARs, considering that during this time some patient and organ motions are unavoidable. Nevertheless, we can consider it clinically deliverable since in our Institute it is available the IGRT Clarity system, a real time prostate tracking through an ultrasound probe that allows a submillimetric accuracy when delivering dose.
In our clinical practice, we use this system for prostate SBRT LINAC based with VMAT technique and we contour targets with the same margin of CK SBRT. [29] Only CK and VMAT were considered eligible for a real treatment because of dose-delivery time, and for both of them the CI and nCI have been measured. These results showed that CI is not exhaustive enough, to have a more complete information about quality and accuracy of the treatment thus the nCI has to be considered. Indeed, even if the CI are not distinguishable, the information about the coverage contained in the nCI allows to affirm that the CK provides better accuracy.
The 3 techniques offer a satisfactory coverage for the PTV in term of 95% and 98% coverage (Table 3) even if a statistically significant difference was found: CK has the highest coverages and VMAT the lowest ones. Moreover, the CK is confirmed to be the most accurate (CI and nCI), the VMAT technique the most rapid and versatile [32] and the lowest HT performance, in terms of time, it can be attributed to its particular way of delivering the dose and to the particular anatomical conformation of this pathology, the HT is particularly suitable for long sized lesions. The differences of the PTV coverages and OARs sparing between CK and VMAT could be attributable to the technological intrinsic properties of the dose delivery. Therefore, by taking into account that CK and VMAT are available solutions for the treatment of prostate cancer and administration of high doses where a suitable tracking system is required, a further study could involve VMAT treatments with the flattening filter free beam in order to have a steepest beam profile comparable to that of CK. Furthermore, it must be taken into account that although CK is the main tool for the SBRT, it is not available in every radiotherapy centers. Thus, VMAT adaptability satisfies the need of hypofractionated treatment of such a widespread disease.
Finally, it is possible to assert that in general there are not big differences among the analyzed techniques if appropriate systems to track the tumor during the treatment are available. As a consequence, if the clinical or anatomical conditions of the patient do not specifically require one technique rather than another, the abovementioned treatments are interchangeable and the best modality to adopt can be evaluated patient by patient.

Study approval and recruiment
This study is part of the Cypro Trial, approved by the Ethics committee of the National Cancer Institute -G. Pascale Foundation -Naples, Protocol Version 1.0; 27th of January 2020. Decision n 105.