A treatment planning study comparing IMRT techniques and cyber knife for stereotactic body radiotherapy of low-risk prostate carcinoma

Different radiotherapy techniques, as well as fractionation regimens, are currently used for localized prostate cancer. A conventionally-fractionated intensity modulated radiotherapy (IMRT) is the most frequently applied treatment modality in the case of prostate cancer. One retrospective analysis evaluated the standard fractionation versus hypofractionation regimens. This analysis suggests that the α/β value for prostate cancer is 1.4 Gy (0.9–2.2) regardless of risk status [1]. Furthermore, hypofractionated radiotherapy (RT) may be radiobiologically favorable in the treatment of prostate cancer due to potentially greater sensitivity of high fraction dose [2‐4]. Previous studies of moderate hypofractionated RT (fraction dose between 2.5 Gy and 3.5 Gy) showed better disease local control, as well as similar toxicity rate compared to conventionally-fractionated RT [5‐7]. Different radiation techniques, additionally, may be applied for stereotactic body RT (SBRT) in order to deliver a large fraction dose to the prostate. RT modality as provided by the robot-assisted technique Cyber Knife® (CK), which can deliver such radiation within a high fraction dose, is currently witnessing increased usage in the treatment of prostate cancer with low-to-intermediate risk [2, 8‐12]. All IMRT techniques, especially rotational approaches as helical tomotherapy (HT) and volumetric modulated arc therapy (VMAT), can potentially deliver a high daily fraction, thus, achieving the treatment plans with high conformity and reducing the dose delivered to the surrounding healthy tissue. In the series of studies a good dosimetric quality for several SBRT techniques for the treatment of localized prostate cancer was demonstrated [13‐17]. In this study, we performed a comparative statistical analysis of dosimetric parameters between Sliding Window (SW), HT, VMAT, and CK for the SBRT in patients with low-risk prostate cancer. It is the first planning study that, specifically, uses the Lyman-Kutcher-Burman (LKB) model in the analysis of late rectal and urinary toxicities following prostate SBRT based on estimation of NTCP parameters.

The volumes of the prostate and urinary bladder did not exhibit any relevant data concerning dose distribution volumetric differences in analyzed patients. The average of these volumes was 31 cm³ (range, 27 cm³ to 58 cm³) and 300 mL (range, 220 mL to 410 mL), correspondingly. Similarly, the rectal diameter did not significantly vary between patients (median 5 cm, range 3.4 cm to 7.4 cm) (Additional file 1: Table S1.

Conformal indices are summarized in Table 3. HI around 0.2 was received for all techniques. The HT provided a higher homogeneity of dose distribution than in any other technique employing the target volume. This demonstrates a significant advantage compared to CK (p = 0.03). Similarly, the coverage index COV appeared inferior for the CK. Other conformity indices (CN, CIICRU_, CΔ) revealed superior values for the CK.

We assessed the dosimetric values for PTV and OAR from the patient-averaged DVH (these values are presented in further detail in Table 4). The mean prescription volumes did not show any relevant volumetric differences between the radiation techniques and varied between 90 cm³ and 160 cm³. The PTVV80 was found significantly lower for CK compared to other IMRT techniques (p = 0.04), whereas D2% and D98% values did not significantly vary between the techniques (Table 4). The patient-averaged DVH revealed statistically superior rectum sparing by IMRT techniques at the doses range of V18 Gy -– 32.6 Gy compared to CK technique (p < 0.05) (Figs. 1 and 2, Table 4). The highest rectum shielding was received by SW at medium-to-high dose range (Figs. 1 and 2, Table 4). The whole urinary bladder experienced the significant shielding by SW and VMAT at 18 Gy (V18 Gy, p < 0.05 versus CK) (Figs. 1 and 2; Table 4). No relevant dosimetric difference in the dose distribution to rectum and urinary bladder was found between techniques at V36.25 Gy. A significantly superior sparing of femoral heads was received by HT (V14.5 Gy). The CK affected mostly the left femoral head, for that spared highly the right femoral head (Figs. 1 and 2; Table 4).

The calculated mean NTCP values and the model parameters for the rectum and urinary bladder are.

listed in Table 5. The HT revealed significantly superior mean NTCP values for rectum (NTCP = 2.3%, p < 0.05) than was demonstrated by VMAT (NTCP = 4.5%), SW (NTCP = 3.8%) and CK (NTCP = 5.8%). For urinary bladder the mean NTCP values were not significantly lower for SW (NTCP = 1.8%) compared to VMAT (NTCP = 2.5%) HT (NTCP = 2.8%) and CK (NTCP = 2.2%). Consequently, the HT demonstrated a lower NTCP outcome compared to CK or IMRT techniques for rectum and the NTCP for the urinary bladder showed no significant advantages for any technique.

Our study evaluated a dosimetric comparison between IMRT-based techniques and robotic-assisted CK system by applying the SBRT for low risk prostate carcinoma. To our knowledge, this is the first time, when the NTCP parameters, which demonstrate probability of late rectal and urinary bladder radiation-related complications, were comparatively analyzed for SBRT techniques. Previous reports showed a high rate of biochemical, disease-free survival, along with an acceptable toxicity profile, with a larger fraction dose by applying SBRT techniques [9, 32‐35]. Most single-center studies have used the CK technology demonstrating the feasibility of CK-based prostate SBRT [9‐13, 33, 35‐38]. McBride et al. demonstrated in their first multi-institutional Phase I study, an effective and safe use of hypofractionation with a CK System, by applying a 7.25–7.5 Gy fraction dose delivered in 5 fractions for the treatment of low-risk prostate adenocarcinoma [12]. The Prospective Randomized Phase III study, “PACE,” was developed to evaluate a clinical outcome following the SBRT monotherapy with CK, and further examined this therapy in comparison to surgery and conventionally fractionated IMRT in localized prostate carcinoma (http://​www.​clinicaltrials.​gov/​ct2/​show/​NCT01584258?​term=​PACE&​rank=​12). Unlike standard IMRT a technique, the CK technology performs an intrafractional matching of the beam targeting the prostate when motion is detected achieving the targeting errors of less than 1 mm [39, 40]. However, the longer treatment time with CK may result in intrafraction dose uncertainty because of bladder and bowel motion with anatomical deformation during the radiation treatment. Thus, Reggiori et al. showed that dose uncertainties for the targets and rectum amplified with the increase of time in patients treated with VMAT [41]. The mean treatment time that we observed for IMRT techniques, especially for VMAT and SW, was significantly less than for CK, (6 and 5 min compared to 42 min, respectively). The short treatment time helps to avoid dosimetric uncertainties in the target volume caused by bladder and bowel intrafraction form variation. Most treatment planning systems used for CK do not have advanced algorithms for the reducing of the planning time. Rossi et al. have proposed an automated treatment plan generation by using of “Erasmus-iCycle” optimizer for the creation of a beam angle class solution for noncoplanar prostate SBRT with CK to replace time-consuming beam angle optimization for each individual patient [16]. Using the in-house developed optimizer, the authors established 15-, 20-, and 25-beam class solutions without significant loss in plan quality compared to individualized beam angle selection, reducing the computation time for the plans generation by a factor of 14 to 25. Thus, using beam angle class solution instead of individualized beam angel selection, 25-beam plans could be generated in 31 min compared with 13 h.

We have demonstrated that both CK and IMRT-based techniques achieve similar dosimeteric outcomes, concerning PTV coverage, as well as providing highly conformal dose distribution. However, PTV homogeneity was significantly lowered in the CK treatment plans compared to rotational IMRT approaches. In addition, the IMRT techniques provided lower rectum and urinary bladder exposure at medium-to-high dose ranges than CK. Our findings are in agreement with the results obtained by MacDougall et al. [13]. Their results were provided from a dosimetric analysis gathered by comparing dose distribution between the CK and a VMAT with delivery of 35 Gy to the prostate in 5 fractions. The dose constraints for OAR were achieved by both techniques, however, PTV homogeneity as well as the mean planning and delivery time were in favor of VMAT. Furthermore, the use of VMAT was found to be superior when sparing OAR at lower radiation doses. Similarly, Lin et al. showed that applying 37.5 Gy in 5 fractions revealed superior PTV coverage and better rectum sparing at low doses with VMAT plans than with CK plans, although 6 MV photon beams were used for the VMAT treatment plans as opposed to 15 MV in our analysis [14]. Moreover, the VMAT plans demonstrated an excellent dose conformity resulting in faster dose falloff compared to CK plans. Finally, the author observed with VMAT plans fewer low-dose area, lower Monitor Units (MU), and faster delivery time than with CK plans. The authors speculated that the overall risk of secondary malignancy might be higher for CK through greater involvement of normal tissue receiving low RT dose, as well as higher MUs and treatment delivery time. Dong et al. comparatively analyzed the dose distribution for prostate SBRT (40 Gy in 5 fractions) by using of optimized robotic non-coplanar RT, termed 4π therapy, which is established on C-arm LINAC platform, and 2-arc VMAT [15]. Both planning methods demonstrated adequate PTV coverage. However, the 4π plans achieved significantly superior sparing of anterior rectum wall and penile bulb, reducing the maximum doses ad V50%, V80%, V90% and D1 cm³. The bladder dose was only slightly reduced by using of 4π therapy. Thus, by optimizing beam angles and fluences in the non-coplanar solution space, the authors have achieved superior quality for prostate SBRT compared to advanced VMAT plans. Rossi et al. developed systems for automatic generation of clinically deliver-able plans for robotic SBRT (autoROBOT). The quality of these plans was compared with VMAT plans that were also automatically generated, by applying of 9.5 Gy in 4 fractions [17]. Interestingly, in the autoROBOT and autoVMAT comparison with 3 mm PTV margins for all techniques, rectum doses (D1 cm³ and Dmean) was significantly lower in autoROBOT plans, with comparable PTV coverage and other OAR sparing. Compared to manual sparing, autoROBOT significantly improved rectum and urinary bladder sparing (D1 cm³ and Dmean), with equal PTV coverage. Thus, in contrast to results observed in our study by the comparison of manually generated VMAT and CK plans, authors demonstrated a superiority of non-coplanar robotic SBRT compared to coplanar VMAT when using the autoplanning for both techniques.

Assuming the same dose objectives for treatment planning, we can explain differences in dose distribution within PTV and OAR by the impact of radiation technique and by different dose calculation algorithms. The Multiplan planning system used for CK is less sensitive to dose constraints than the planning systems used for rotational approaches. Lowered sensitivity can result in the difference of PTV homogeneity in CK plans while using the same dose objectives in the planning system for IMRT techniques. However, a crucial factor that determinates the feasibility of radiation treatment plans is the optimization of dose constraints in each individual case.

Varying selection criteria, as well as differences in the target volume definition and dose constraints for OAR that do exist, actually describe the prostate SBRT. The difference in a cumulative radiation dose (between 33 Gy and 38 Gy), as well as in RT regimens (4 to 5 fractions) lead to substantial variations in an applied BED. Similarly, there is a wide spectrum of dose constraints for PTV and OAR in the available literature date [2, 7‐9, 42‐44]. For this reason, we used a combination of constraints from the PACE study and those recommended by Accuray and Varian Centers which deliver SBRT with CK/tomotherapy and RA/Sliding Window, consecutively. We assessed the BED by using the α/β value of 3 for rectum and 6 for urinary bladder to convert all constraint dose to 2 Gy per fraction. This allowed for an appreciation of the used dose objectives, according to criteria proposed by QUANTEC reports, which establishes the conventionally fractionated RT [19, 20]. Concerning the urethral sparing, is suggested that more heterogeneous dose distribution may provide a requisite prostatic urethra sparing within PTV. We restricted the maximum dose to 110% of the prescription dose in the treatment plans for all techniques to reduce the irradiation dose for the prostatic urethra. In the aspect of urethral toxicity, a multicentric Phase II study, which evaluates the SBRT in prostate cancer delivered by VMAT, including urethral sparing, is ongoing (http://​www.​clinicaltrials.​gov/​ct2/​show/​NCT01764646?​term=​NCT01764646&​rank=​1). Generally, the dose objectives for the prostate SBRT should be based on the datasets of the advanced radiotherapy technologies and large prospective randomized trials.

Another concern is the safety margins in the PTV delineation, which should be used to deliver SBRT for low-risk prostate carcinoma, to achieve a validated dosimetric comparison we used the same safety margins in both the CK and IMRT techniques, with a 3 mm margin in the dorsal direction and 5 mm margin in ventral and lateral directions. The use of image-guided RT with prostate verification immediately before treatment may not be enough for the precise delivery of radiation dose due to intrafraction prostate motion. According to established literature, the standard deviation of systematic and random errors due to intrafraction prostate motion varies from 0.2 to 1.7 mm and 0.4 to 1.3 mm, respectively [41, 45‐49]. Considering that CK performs the real-time tracking of intrafractional prostate motion with a 1 mm precision in radiation dose delivery, MacDougall et al. have suggested the use of a safety margin of 3 mm for all directions in CK and 5 mm in VMAT [13]. Some authors observed a good clinical response as well as very low risk of intestinal grade 4 and 3 adverse effects applying the CK-based SBRT for low-risk prostate carcinoma by using of 2 or 2.5 mm safety margins into the rectal directions [50, 51]. Similarly, in the newly initiated prospective observational bi-center trial “HYPOSTAT”, the PTV was delineated with posterior margins of 2 mm for the CK-based SBRT [52]. On the other side, in the large series of reports describing the stereotactic RT with CK for localized prostate carcinoma, was observed a low rate of transient grade 3 and 2 urinary and rectal toxicities by using of 3 mm dorsal PTV margin and 5 mm safety margins in all other directions [41, 45‐49]. Considering the highest exposure of rectum and urinary bladder for CK compared to IMRT that was revealed in this study, we would recommend reducing the PTV margins up to 2 mm in all directions for the CK-based SBRT, to minimize the risk of urinary and rectal toxicities as well as to provide a dosimetric advantage compared to advanced IMRT techniques.

One lingering question in regards to SBRT for prostate cancer is the RT regimen. King et al. reported on the fourfold reduction in Grade 1 urinary toxicity and a sevenfold reduction in Grade 1 rectal toxicity in favor of the every-other-day SBRT compared to daily SBRT consisted of 36.25 Gy in 5 fractions [9]. The authors, ultimately, recommended treating the prostate with an every-other-day dose schedule in order to allow the SBRT to minimize late effects in normal tissue. However, only a randomized trial would be able to properly study differences between different RT regimens.

We focused on analyzing the probability of late rectal and urinary toxicities by using SBRT on low-risk prostate carcinoma. Despite the significant dosimetric advantage in rectum protection for SW (Table 4), the NTCP values of late rectal toxicities reveal that HT is superior in this regard (Table 5). Use of fixed-fields IMRT, but not rotational techniques, was shown to improve the NTCP parameters for urinary bladder. The SW or HT, but not VMAT, generally are preferred in order to reduce the probability of late rectal in the treatment of low-risk prostate carcinoma. The NTCP for the urinary bladder showed no significant advantages for any technique.

This study is based on the treatment planning systems Eclipse™10, Tomo planning system version 5 and the Multiplan® planning system version 5.2. In the development process of this work the treatment planning systems were routinely used in our institute. The newer algorithms for the optimization lead into a different way of planning. For example the new Photon Optimizer in the Eclipse™15 has an improved OAR and target overlap modeling. With similar dose objectives in the planning process the resulting dose distribution and DVH differs slightly between Eclipse™10 and Eclipse™15. Therefore, the individual optimization of dose objectives may improve the target coverage and OAR sparing by using of Eclipse™10 treatment planning system. The NTCP values are based on DVH results so a newer algorithm could show a different result. There are some studies about the influence or impact of dose calculation algorithms on NTCP values, especially for lung cancer [53‐55]. Because of a steady progress of algorithms to increase the accuracy of dose distribution and to minimize uncertainties, an additional work could investigate the impact of an update of the Eclipse™10 to Eclipse™15 regarding the NTCP of prostate SBRT.

Our study is limited by its retrospective nature and small number of study population which precludes big conclusions and planning’s parameters used should not be extrapolated for all cases. For example, the PTV margins for prostate SBRT should be defined based on radiation technique used, carcinoma stage and prostate volume. Another possible limitation is selection bias due to large difference in the prostate and rectal volume in analyzed patients (Additional file 1: Table S1. For this reason, the estimated treatment plans demonstrated large variations in the values of PTV coverage and OAR sparring between patients. In addition, the dose constraints for rectum and urinary bladder recommended by QUANTEC are based on 3-D conventional RT datasets. The advanced IMRT and CK techniques provide highly conformal dose distribution, performing superior OAR sparing compared to 3-D CRT, thus the dose constraints for OAR must be adopted for advanced IMRT and CK techniques used for prostate SBRT. Regarding NTCP analysis, we used the Lyman’s model of rectal and bladder toxicities for estimating of NTCP values. However, Viswanathan et al. aver that no convenient quantitative model exists, which can satisfactorily analyze late bladder toxicity after external beam radiotherapy [20]. This is due to lack of a clear dose response and functional variability of the bladder. Finally, the radiation plans can be optimized by individual modification of dose objectives for each treatment case. This argument can diminish the relevance of the obtained results, despite the use of similar dose objectives in the estimation of the radiation plans. Thus, selection criteria for dosimetric comparison between different radiation approaches should be further optimized.

This analysis is focused on the evaluation of the dosimetric feasibility of different SBRT techniques in the therapy of low-risk prostate cancer. For all techniques we applied the same safety margins for the delineation of the target volume as well as the same dose objectives were used for the plan optimizations. Major findings to emerge from this study are as follows: (i) All techniques showed a high conformal dose distribution in achieving OAR constraints; (ii) The CK revealed lower homogeneity within the target volume; (iii) The CK revealed the highest exposure of rectum and urinary bladder compared to IMRT, especially at medium-to-high dose ranges; (iv) comparing IMRT techniques, the SW displayed superior rectum sparing at medium-to-high dose range, whereas both SW and VMAT revealed superior bladder sparing; (v) techniques such as SW or HT — but not VMAT — demonstrate a reduced probability of late rectal complications; (vi) The mean treatment delivery time was significantly less for IMRT techniques than for CK, with shorter mean values for SW (6 min) and VMAT (5 min) compared to 42 min for CK. Generally, this dosimetric analysis revealed a higher protection of the rectum and bladder by using IMRT techniques compared to CK for the SBRT of prostate cancer. However, considering the possible optimization of radiation plans by the individual modification of dose objectives for each case, the radiation technique for prostate SBRT should be selected individually dependent on the treatment strategy.