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Evaluation of plan robustness on the dosimetry of volumetric arc radiotherapy (VMAT) with set-up uncertainty in Nasopharyngeal carcinoma (NPC) radiotherapy

Evaluation of plan robustness on the dosimetry of volumetric arc radiotherapy (VMAT) with set-up... Purpose: To evaluate the sensitivity to set up the uncertainty of VMAT plans in Nasopharyngeal carcinoma (NPC) treatment by proposing a plan robustness evaluation method. Methods: 10 patients were selected for this study. A 2-arc volumetric-modulated arc therapy ( VMAT ) plan was gener- ated for each patient using Varian Eclipse (13.6 Version) treatment planning system ( TPS). 5 uncertainty plans (U-plans) were recalculated based on the first 5 times set-up errors acquired from cone-beam computer tomography (CBCT ). The dose differences of the original plan and perturbed plan corresponded to the plan robustness for the structure. Tumor control probability ( TCP) and normal tissues complication probability (NTCP) were calculated for biological evaluation. Results: The mean dose differences of D and D (ΔD and ΔD ) of PTVp were respectively 3.30 Gy and 98% 95% 98% 95% 2.02 Gy. The ΔD and ΔD of CTVp were 1.12 Gy and 0.58 Gy. The ΔD and ΔD of CTVn were 1.39 Gy and 98% 95% 98% 95% 1.03 Gy, distinctively lower than those in PTVn (2.8 Gy and 2.0 Gy). The CTV-to-PTV margin increased the robustness of CT Vs. The ΔD and ΔD of GTVp were 0.56 Gy and 0.33 Gy. GTVn exhibited strong robustness with little variation 98% 95% of D (0.64 Gy) and D (0.39 Gy). No marked mean dose variations of D were seen. The mean reduction of TCP 98% 95% mean (ΔTCP) in GTVp and CTVp were respectively 0.4% and 0.3%. The mean ΔTCPs of GTVn and CTVn were 0.92% and 1.3% respectively. The CTV exhibited the largest ΔTCP (2.2%). In OARs, the brain stem exhibited weak robustness due to their locations in the vicinity of PTV. Bilateral parotid glands were sensitive to set-up uncertainty with a mean reduc- tion of NTCP (ΔNTCP) of 6.17% (left) and 7.70% (right). The D of optical nerves and lens varied slightly. max Conclusion: VMAT plans had a strong sensitivity to set-up uncertainty in NPC radiotherapy, with increasing risk of underdose of tumor and overdose of vicinal OARs. We proposed an effective method to evaluate the plan robustness of VMAT plans. Plan robustness and complexity should be taken into account in photon radiotherapy. *Correspondence: dingzhen0909@163.com; xiangxiaoyong16@163.com Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 113 Baohe Rd, Longgang District, Shenzhen City 518116, Guangdong Province, People’s Republic of China © The Author(s) 2021. 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The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ding et al. Radiation Oncology (2022) 17:1 Page 2 of 10 Keywords: Robustness, Tumor control probability, Normal tissue complication probability, Set-up uncertainty Introduction Methods Radiotherapy (RT) is the main strategy for Naso- Patient selection and delineation pharyngeal carcinoma (NPC) [1]. Owing to large irra- We retrospectively evaluated treatment plans for 10 NPC diation volumes, complex and intricate anatomical patients treated in our center. The clinical characteris - structures, precision dose coverage, and organ at risk tics of the patients enrolled in this study were shown in (OAR) sparing were crucial in NPC radiotherapy [2]. Table  1. All the patients were immobilized by a thermo- Volumetric arc radiotherapy (VMAT) had been widely plastic mask in a supine position. The CT image with a used in NPC radiotherapy, for VMAT performed opti- 2.5 mm slice thickness was acquired using a 16-slice CT mized dose distribution and OAR sparing by con- scanner (GE Discovery RT, GE Healthcare, Chicago, IL, tinuous variation of multi machine parameters [3]. USA). The target volumes and organs at risk (OARs) were However, increased plan complexity elevated risk of delineated by the same clinician. The gross tumor volume dose calculation and delivery, for more complex plans (GTV) consisted of GTV of the primary (GTVp) and required smaller and irregular beam apertures, larger GTV of lymph nodes (GTVn). The clinical target volume tongue-and groove effects, and greater extent modula- (CTV) consisted of CTVp and CTVn. The planned tar - tion of machine parameters, including gantry rotation get volume (PTV) included PTVp, PTVn, and PTV. All speed, dose rate, and multi leaf collimator (MLC) posi- the GTVs, CTVs, and PTVs were contoured by the same tion [4, 5]. VMAT plans may show the sensitivity of oncologist based on international guidelines [10]. dose delivery to subtle deviations, including machine parameters and target motion [4, 6]. Image guidance, such as the cone-beam computed Treatment plans and uncertainty plans tomography (CBCT) has been widely used in posi- A 2-arc volumetric-modulated arc therapy (VMAT) plan tion verification to reduce patient set-up uncertainty was generated for each patient using Varian Eclipse (13.6 [7]. The protocol of imaging frequency varies among Version,) treatment planning system (TPS) modeled for centers to balance the treatment efficiency and accu- the VitalBeam (Varian, Palo Alto, US) linac. Arc 1 (A1) racy. The unknown remaining fractions may result in rotate clockwise from 181° to 179°, and the arc 2 (A2) unexpected dose deviation and potential tumor recur- rotates counterclockwise from 179° to 181°. Collimator rence [8]. For this purpose, we aimed to study the sen- angles were set at ± 10°. The prescription doses of PTVp, sitivity of highly optimized VMAT plans to geometry PTVn, and PTV were 69.96 Gy, 68.31 Gy, and 59.40 Gy in deviation to make a more complete description of dose 33 fractions, respectively. delivery for complex plans. 5 set-up uncertainties were introduced on the origi- Treatment plan robustness is the degree of resiliency nal VMAT plan, shifting the isocenter from its refer- of the required dose distribution to these uncertain- ence position according to the set-up errors acquired by ties and varies with the treatment site, technique, and CBCT. The U-plans, representing the perturbed plans method. Yock’s [9] report reviewed robustness analysis introduced set-up uncertainties, were calculated for 33 methods and their dosimetric effects, to promote reli- able plan evaluation and dose reporting, particularly during clinical trials conducted across institutions and Table 1 Patients characteristics treatment modalities. The concept of robustness had Patient # Age Sex Stage been widely used in proton treatment plans for the sharp distal fall-off and scattering characteristics but 1 57 Male T1N1M0 was ignored in photon radiotherapy [5]. We adopted a 2 62 Male T4N2M0 plan robustness quantification method to address the 3 68 Male T3N2M0 sensitivity of VMAT plans to geometric uncertainty 4 27 Male T1N2M0 based on the daily CBCT shifts. Besides, the tumor 5 28 Female T1N1M0 control probability (TCP) and normal tissues com- 6 68 Male T1N1M0 plication probability (NTCP) models were applied to 7 67 Male T2N2M0 evaluate the potential biological dose differences. 8 43 Male T3N0M0 9 54 Male T1N1M0 10 38 Male T1N1M0 Ding  et al. Radiation Oncology (2022) 17:1 Page 3 of 10 Table 2 Evaluated items of PTVs and OARs from the maximum value and corresponded to the plan robustness for the structure. PTVs/OARs Evaluated items PTVp, PTVn, PTV ΔD , ΔD , 2cc 98% TCP and NTCP evaluation ΔD , ΔD 95% mean, Biological models have been proposed to predict radio- ΔTCP biological response to dose after irradiation [11, 12]. The CTVp, CTVn, CTV TCP and NTCP values were calculated to evaluate the GTVp, GTVn biological effects. We use the Schultheiss logit model pro - Brain Stem, Brain Stem PRV ΔD ΔNTCP max, posed by Niemierko [13]. We calculated the TCP accord- Spinal Cord, Spinal Cord PRV ing to Eq.  (1) with the parameters: T CD = 61.59  Gy, Lens L, Lens R γ = 3.38 [14]. Optic Nerve L, Optic Nerve R, Optic Chiasma Parotid L, Parotid R ΔD ΔNTCP mean, 1 TCP = 4γ PTV, planning target volume; PTVp, planning target volume of GTVp; PTVn, 50 (1) TCD 1 + planning target volume of GTVn; CTV, clinical target volume; CTVp, primary EUD tumor sites and their invasion range; CTVn, the clinical target volume of GTVn; GTVp, the clinical target volume of GTVp; GTVn, cervical metastatic lymph TCD is the dose of radiation that locally controls 50% node. D and D represented the mean dose and the maximum dose. D 50 mean max x% represented the dose (in Gy) received by x% of the volume, V the volume (in of tumors. The γ is the change in TCP expected because y Gy percentage) received by y Gy. D the dose (in Gy) received by a volume of 2 2cc of a 1% change in dose about the T CD . We calculated cm the NTCP [14] according to Eq. (2) x−TD ( ) EUD 2σ (2) NTCP = √ ∫ e dx σ 2π −∞ The σ was calculated by Eq. (3) σ = mTD 50 (3) The EUD, representing equivalent uniform dose, was calculated according to Eq. (4)   V D  i  i i EUD = �   (4) Fig. 1 Steps in robustness and biological evaluation of volumetric arc radiotherapy ( VMAT ) of NPC. U1 ~ U5 represented 5 set-up TD is the tolerance dose yielding a 50% complica- uncertainties acquired from the first 5 times daily CBCT. T-plan: tion rate in the normal organ. V is the volume at dose D . i i Treatment plan; U-plan: Uncertainty plan Parameter m and n are specific dose–response constants [15]. Statistical analysis fractions to facilitate the dose comparison. The evaluated There are 1  T-plan and 5 U-plans for each patient. The items of PTVs and OARs were listed in Table 2 (Fig. 1). dose differences were calculated by the absolute value of the minimum value subtracted from the maximum value and were explicit by mean value (minimum value to max- Robustness quantification method imum value). The dose deviations of D, D, D , and 95% 98% 2cc There are 1 treatment plan (T-plan) and 5 uncertainty D of CTVs, GTVs, and PTVs were chosen. D was mean max plans (U-plans) for each patient. The dose values in the chosen for serial OARs and D for the bilateral parotid mean treatment and perturbed plans were displayed in the gland. The TCP and NTCP reduction were calculated. dose-volume histogram (DVH) curves. D represented x% the dose (in Gy) received by x% of the volume. D the 2cc 3 Results dose (in Gy) received by a volume of 2 c m. D and max Targets dose coverage D represented the maximum and mean dose (in mean Figure  2 shows a schematic of transversal dose distribu- Gy). Absolute differences ΔD, which could be calculated tions in 1 treatment plan and 5 U-plans. The transver - by the absolute value of the minimum value subtracted sal dose coverage varies due to set-up uncertainty. To Ding et al. Radiation Oncology (2022) 17:1 Page 4 of 10 visualize the dose difference, a color wash schematic of 3.30  Gy and 2.02  Gy. Decreased ΔD (1.12  Gy) and 98% differences in dose distributions is shown in Fig.  3. The ΔD (0.58  Gy) were seen in CTVp. The ΔD and 95% 98% maximum dose discrepancies were observed in marginal ΔD in GTVp were 0.56 Gy and 0.33 Gy, indicating that 95% zones of PTVs. The dose changes of OARs were also the CTV-to-PTV margin promoted the robustness of greater in the vicinity of marginal zones and lesser distal GTV and CTV. Similarly, the PTVn had the largest differ - to these areas. ence of D (2.77 Gy) and D (2.00 Gy). The ΔD and 98% 95% 98% The average dose difference was shown in Table  3. No ΔD of CTVn were 1.39 Gy and1.03 Gy. Minor dose dif- 95% obvious differences were found in D The mean dose ferences were observed in GTVn for both D (0.64 Gy) 2cc. 98% differences of D and D of PTVp were respectively and D (0.59  Gy). No marked mean dose variations of 98% 95% 95% Fig. 2 A schematic of transversal dose distributions in 1 treatment plan and 5 U-plans. The green volume represents PTV, the brown volume represents PTVn, and the red volume represents PTVp. The transversal dose coverage varies due to set-up uncertainty Fig. 3 An example of color wash schematic of dose difference bewteen the T-plan and one of the U-plan. The green, brown, and red volumes represent PTV, PTVn, and PTVp respectively Table 3 Dose difference of PTVs, CTVs, and GTVs in 10 patients Targets ΔD (Gy) ΔD (Gy) ΔD (Gy) ΔD (Gy) 2cc 98% 95% mean PTVp 0.23 (0.07–0.34) 3.30 (0.76–4.38) 2.02 (0.53–3.23) 0.31 (0.11–0.70) PTVn 0.36 (0.05–0.86) 2.77 (0.60–6.05) 2.00 (0.72–4.56) 0.65 (0.10–1.52) PTV 0.18 (0.03–0.35) 1.95 (0.26–3.20) 1.34 (0.27–2.01) 0.35 (0.05–0.57) CTVp 0.20 (0.04–0.35) 1.12 (0.38–3.85) 0.58 (0.23–1.50) 0.16 (0.05–0.30) CTVn 0.40 (0.08–0.75) 1.39 (0.17–5.81) 1.03 (0.43–4.10) 0.56 (0.12–1.43) CTV 0.19 (0.03–0.34) 1.17 (0.12–2.44) 0.72 (0.11–1.51) 0.28 (0.06–0.46) GTVp 0.28 (0.12–0.37) 0.56 (0.06–2.88) 0.33 (0.07–0.67) 0.22 (0.03–0.49) GTVn 0.39 (00.16–0.74) 0.64 (0.30–1.91) 0.59 (0.16–1.59) 0.44 (0.08–0.84) The results were exhibited by Mean (Minimum–Maximum) Ding  et al. Radiation Oncology (2022) 17:1 Page 5 of 10 Table 4 Dose difference of D or D in OARs in 10 patients D were seen. Superior robustness in PTV and CTV max mean mean was seen. Items OARs Dose (Gy) Table  4 showed the dose differences of OARs. ΔD Brain Stem 4.34 (1.50–11.10) max The ΔD of the brain stem and PRV were 4.34  Gy max Brain Stem PRV 6.21 (2.40–10.19) (1.50  Gy-11.10  Gy) and 6.21  Gy (2.40  Gy-10.19  Gy). Spinal Cord 2.86 (1.00–7.10) The ΔD of the spinal cord and PRV were 2.86  Gy max Spinal Cord PRV 3.54 (1.70–7.40) (1.00  Gy-7.10  Gy) and 3.64  Gy (1.70  Gy-7.40  Gy). Nar- Lens L 0.89 (0.20–2.80) rowed width of DVH bands was observed in the bilateral Lens R 0.79 (0.20–1.40) lens. Optical nerves performed marked dose difference Optical Nerve L 8.00 (1.80–17.40) of mean dose, which were 8.00 Gy, 8.66 Gy, and 8.81 Gy Optical Nerve R 8.66 (1.40–20.20) for optical nerve L,R, and chiasma. The D of bilateral mean Optic Chiasma 8.81 (1.80–20.80) parotid glands exhibited obvious changes. ΔD Parotid L 4.48 (2.47–7.28) A sample of dose-volume histograms (DVHs) of mean Parotid R 4.05 (2.01–6.00) PTVs, CTVs, and GTVs was shown in Fig.  4. The solid line represented the DVH of the treatment plan, and The results were exhibited by Mean (Minimum–Maximum) the 5 dashed lines represented the DVH of U-plans. The envelope was defined as the area between all the DVH Fig. 4 A sample of dose-volume histograms (DVHs) of PTVs, CTVs, and GTVs, compared for 1 treatment plan and 5 U-plans. The DVH curve in the solid line represented the treatment plan. The DVH curves in the dashed line represented 5 U-plans. A PTVp; B PTVn; C PTV; D CTVp; E CTVn; F CTV; G GTVn; H GTVp Ding et al. Radiation Oncology (2022) 17:1 Page 6 of 10 curves. The gradually narrowed envelope was seen in Superior robustness was seen in PTV (Fig.  4C) and PTVp (Fig.  4A), CTVp (Fig.  4D), and GTVp (Fig.  4G). CTV (Fig. 4F). PTVn (Fig.  4B) exhibited high sensitivity to set-up As to OARs (Fig.  5), the brain stem (Fig.  5A) and uncertainty. Narrowed width of the envelope was its PRV (Fig.  5B) exhibited weak robustness due to seen in CTVn (Fig.  4E). Sufficient dose coverage and their locations in the vicinity of PTVs. The spinal cord decreased robustness were noticed in GTVn (Fig.  4H). (Fig. 5C) and its PRV (Fig. 5D) had stronger robustness. Fig. 5 A sample of dose-volume histograms (DVHs) of OARs was compared for 1 treatment plan and 5 U-plans. The DVH curve in the solid line represented the treatment plan. The DVH curves in the dashed line represented 5 U-plans. A Brain Stem; B Brain Stem PRV; C Spinal Cord; D Spinal Cord PRV; E Parotid L; F Parotid R; G Optical Nerve L; H Optical Nerve R; I Optical Nerve Chimsa; J Lens L; K Lens R Ding  et al. Radiation Oncology (2022) 17:1 Page 7 of 10 Bilateral parotid glands (Fig.  5E. F) were sensitive to Discussion set-up uncertainty for their being partially enclosed VMAT plans exhibited strong sensitivity to geomet- PTVs. The D of bilateral optical nerves (Fig.  5G–I) ric deviation PTVp and PTVn with large ΔD and max 98% and lens(Fig. 5J, K) varied slightly. ΔD . In photon radiotherapy, the CTV-to-PTV mar- 95% gin method was adopted based on the Van Herk margin formula [16] in the margin-based treatment planning, to TCP and NTCP evaluation ensure the dose coverage of CTV by blurring dose distri- The TCP reduction (ΔTCP) was the mean absolute bution induced by systematic setup errors. Although the value of the minimum value subtracted from the maxi- CTV-to-PTV margin increased robustness in CTVp and mum value. For GTVp and CTVp, the ΔTCP value CTVn, the ΔD of CTVp and CTVn reached 1.12  Gy 98% was less than 1% (Fig.  6), indicating strong robust- and 1.39  Gy. The ΔD of GTVp and GTVn reached 98% ness to set-up uncertainty. A greater ΔTCP value was 0.56  Gy and 0.64  Gy. Similarly, considerable dose devia- observed in GTVn and CTVn. CTV had the largest tions were observed in D of CTVp, CTVn, PTVp, and 95% TCP reduction. PTVn. Although the margin method effectively improved We performed NTCP modeling analysis to evaluate the plan’s robustness by reducing sensitivity to the uncer- the dose variation of OARs (Fig.  7). The NTCP reduc - tainties, high risk remains. The dose variation of D and 95% tion (ΔNTCP) was obtained as the mean absolute value D in PTVs could reach a maximum of 6 Gy. The maxi - 98% of the minimum value subtracted from the maximum mum difference of D and D in CTVs and GTVs 95% 98% value. The average ΔNTCP of bilateral parotids reached could reach a maximum of 2.81  Gy. The maximum dif - 6.17% (left) and 7.70% (right) (Fig.  7). No significant ference of D of PTVs could reach 1.5  Gy. The study mean biological dose changes were found in OARs. of Dupic [17] indicated that the GTV D is a strong 98% reproducible significant predictive factor of local control for the brain. A sufficient dose of GTVs should be rigidly reached. Zhao et al. [18] performed a retrospective study of a total of 1,092 patients with NSCLC of clinical-stage T1-T2 N0M0 who were treated with SABR. They rec - ommended that both PTV D and PTV should be 95% mean considered for plan optimization other than gross tumor volume. When the physical dose changed, the biologi- cal effect followed. The ΔTCP in GTVp and CTVp were respectively 0.4% and 0.3%. However, ΔTCP of GTVn and CTVn were 0.92% and 1.3% respectively. The CTV had the largest mean variation of ΔTCP (2.2%). Under dosage in the targets may result in the likelihood of Fig. 6 Box plot showed the ΔTCP of all targets due to set-up tumor recurrence [19], for TCP predominately correlates uncertainties. The ΔTCP was the mean reduction of TCP Fig. 7 Box plot showed the ΔNTCP of OARs due to set-up uncertainties. The ΔNTCP was the mean reduction of NTCP Ding et al. Radiation Oncology (2022) 17:1 Page 8 of 10 with the minimum dose of tumor [13]. Plan robustness of Plan robustness qualification was always considered in photon radiotherapy should be taken into consideration. proton therapy to address sensitivity to uncertainties in Weak robustnesses and large dose variations were treatment planning [29]. In photon RT, the CTV-to-PTV observed in the OARs in the vicinity locations of PTVs. margin method had been adopted to assure dose cov- In this study, the average ΔD of the brain stem and spi- erage with uniform margin, instead of plan robustness max nal cord reached 1.85 Gy and 1.51 Gy. Previous research qualification. However, the CTV-to-PTV margin method reported that brain stem necrosis, MIR-based evidence has limitations, such as relying on the so-called static of injury, or neurologic toxicities were related to pho- dose cloud approximation. A phantom study conducted ton radiotherapy [20–22]. Using conventional fractiona- by Englesman et al. [30] observed a maximum decreased tion of 1.8–2  Gy/fraction to the full-thickness cord, the dose of 5% with respiratory motion uncertainty. Guer- estimated risk of myelopathy is < 1% and < 10% at 54  Gy reiro [31] evaluated the robustness against inter-fraction and 61  Gy, respectively [23]. For bilateral optic nerves anatomical changes between photon and proton dose and chiasm, the average ΔD were 4.59  Gy, 5.00  Gy distributions and found that daily anatomical changes max and 5.01 Gy. There is a shred of strong evidence that evi - proved to affect the target coverage of VMAT dose dis - dence radiation tolerance is increased with a reduction tributions to a higher extent. Our results indicated that in the dose per fraction [14, 24]. In radiotherapy of NPC, CTV-to-PTV margin increased robustness of CTV and the bilateral parotids are often under irradiation. Sali- GTV, reduced but did not remove the risk of underdos- vary dysfunction has been correlated to the mean parotid age. This plan robustness quantification method could be gland dose, with recovery occurring with time [25–27]. adopted in highly optimized clinical treatment plans to The average ΔNTCP of bilateral parotids reached 6.17% make a more complete dose description. (left) and 7.70% (right), which sharply increased the risk Besides, the robustness optimization methods had of parotid gland dysfunction. The actual irradiation dose been developed by incorporating uncertainty in plan of vicinal OAR may be biased upwards due to the set-up optimization, for CTV should receive the prescribed dose uncertainty. depending on desired dose distribution and dose fall-off Based on the results in this study, it is not hard to near the target rather than geometric margin [32]. Lowe notice the strong sensitivity of highly optimized VMAT et al. [33] believed robustness optimization was an effec - plans to geometric deviations. This generates worries tive method to reduce dose to normal tissues that would about the accuracy of treatment dose delivery. ‘Plan be unnecessarily irradiated with the CTV-to-PTV mar- quality assessment’ had been proposed firstly by the 3rd gin concept. Dosimetric consequences of uncertainty, Physics ESTRO Workshop in 2019. Plan quality could such as equivalent uniform dose (EUD), TCP, and NTCP be understood as the clinical suitability of the delivered were also recommended. dose distribution that can be realistically expected from Among the limitation of the study, it is important to a treatment plan [4]. Plan quality depends on the plan highlight that the first 5 times set-up errors acquired robustness and complexity of the treatment plan. from CBCT did not represent the actual set-up uncer- Intricate anatomical structures, precise dose coverage, tainty, for the set-up error consisted of systematic and and optimal OARs sparing generated highly optimized random errors. Additionally, the patient anatomy change VMAT plans in NPC radiotherapy. High-degree modu- and rotation have not been taken into account. As a pos- lated radiotherapy techniques increased plan complexity, sible solution, adaptive radiotherapy (ART) could help to with modulation of machine parameters, such as gantry solve this problem [34]. We aimed to simulate the scenar- rotate speed, continuously varied dose rate, and position ios introduced to set up uncertainties, and visualize the of MLC. A study by Hirashima [28] uses plan complex- necessity of robustness quantification is highly optimized ity and dosiomics features to predict the performance for photon RT. Treatment plan robustness analysis provides gamma passing rate, indicating the correlation between a more complete description of the dose delivered in the plan complexity and the accuracy of treatment plan dose presence of uncertainties, and may lead to future dosi- delivery. Many commercial TPSs now offer the possibil - metric studies with improved accuracy. ity to control plan complexity, such as controlling the minimum size and monitor unit (MU) (Phillips Pinnacle, Conclusions Amsterdam, the Netherlands), aperture shape controller VMAT plans had a strong sensitivity to set-up uncer- (ASC) (Varian Eclipse, Palo Alto, CA, USA), and modu- tainty in NPC radiotherapy, due to the high degree of lation factor (MF) (TomoTherapy, Accuray Incorporated, modulation. We proposed an effective method to evalu - Sunnyvale, CA, USA). The balance should be reached ate the plan robustness of VMAT plans. Plan robustness between dosimetric improvement and dose delivery and complexity should be taken into account in photon accuracy. radiotherapy techniques with high degree optimization. Ding  et al. Radiation Oncology (2022) 17:1 Page 9 of 10 5. Korevaar EW, Habraken SJM, Scandurra D, et al. Practical robustness The robust optimization may have the potential and evaluation in radiotherapy—a photon and proton-proof alternative to could be considered in complex plans with a reliable eval- PTV-based plan evaluation. Radiother Oncol. 2019;141:267–74. https:// uation of long-term clinical outcomes. doi. org/ 10. 1016/j. radonc. 2019. 08. 005. 6. Hubley E, Pierce G. The influence of plan modulation on the interplay effect in VMAT liver SBRT treatments. Phys Med. 2017;40:115–21. https:// doi. org/ 10. 1016/j. ejmp. 2017. 07. 025. Abbreviations 7. Boda-Heggemann J, Lohr F, Wenz F, Flentje M, Guckenberger M. kV PTV: Planning target volume; PTVp: Planning target volume of GTVnx; PTVn: cone-beam CT-based IGRT: a clinical review. Strahlenther Onkol. Planning target volume of GTVnd; CTV: Clinical target volume; CTVp: Primary 2011;187(5):284–91. https:// doi. org/ 10. 1007/ s00066- 011- 2236-4. tumor sites and their invasion range; CTVn: The clinical target volume of 8. Wang H, Huang Y, Hu Q, et al. A simulated dosimetric study of contribu- GTVn; GTVp: The clinical target volume of GTVp; GTVn: Cervical metastatic tion to radiotherapy accuracy by fractional image guidance protocol of lymph node; CBCT: Cone beam computed tomography; VMAT: Volumetric arc halcyon system. Front Oncol. 2021;10:543147. https:// doi. org/ 10. 3389/ radiotherapy; IMRT: Intentively modulated radiotherapy; 3D-CRT : 3-Dimension fonc. 2020. 543147. conformal radiotherapy; OAR: Organs at risk; TCP: Tumor control probability; 9. Yock AD, Mohan R, Flampouri S, et al. Robustness analysis for external NTCP: Normal tissues complication probability. beam radiation therapy treatment plans: describing uncertainty sce- narios and reporting their dosimetric consequences. Pract Radiat Oncol. Acknowledgements 2019;9(4):200–7. https:// doi. org/ 10. 1016/j. prro. 2018. 12. 002. Not applicable. 10. Lee AW, Ng WT, Pan JJ, et al. International guideline for the delineation of the clinical target volumes (CTV ) for nasopharyngeal carcinoma. Radio- Authors’ contributions ther Oncol. 2018;126(1):25–36. https:// doi. org/ 10. 1016/j. radonc. 2017. 10. ZD: Methodology, Data Curation; Writing; XX: Conceptualization, Methodol- ogy; QZ, JM: Data Curation and preparation of tables; ZD, KK, SB: Preparation of 11. Liu F, Tai A, Lee P, et al. Tumor control probability modeling for stereo- figures. All authors read and approved the final manuscript. tactic body radiation therapy of early-stage lung cancer using multiple bio-physical models. Radiother Oncol. 2017;122(2):286–94. https:// doi. Funding org/ 10. 1016/j. radonc. 2016. 11. 006. The research was supported by Sanming Project of Medicine in Shenzhen 12. Jakobi A, Lühr A, Stützer K, et al. 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Significant correlation between gross The patients gave their informed consent for use of the data for research tumor volume (GTV ) D98% and local control in multifraction stereotactic purposes. radiotherapy (MF-SRT ) for unresected brain metastases. Radiother Oncol. 2021;154:260–8. https:// doi. org/ 10. 1016/j. radonc. 2020. 11. 021. Competing interests 18. Zhao L, Zhou S, Balter P, et al. Planning target volume D95 and mean The authors state that they have no competing interests. dose should be considered for optimal local control for stereotactic abla- tive radiation therapy. Int J Radiat Oncol Biol Phys. 2016;95(4):1226–35. Received: 30 August 2021 Accepted: 17 December 2021 https:// doi. org/ 10. 1016/j. ijrobp. 2016. 01. 065. 19. Lu JY, Lin Z, Zheng J, Lin PX, Cheung ML, Huang BT. Dosimetric evaluation of a simple planning method for improving intensity-modulated radio- therapy for stage III lung cancer. Sci Rep. 2016;6:23543. https:// doi. org/ 10. 1038/ srep2 3543. 20. 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Evaluation of plan robustness on the dosimetry of volumetric arc radiotherapy (VMAT) with set-up uncertainty in Nasopharyngeal carcinoma (NPC) radiotherapy

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Abstract

Purpose: To evaluate the sensitivity to set up the uncertainty of VMAT plans in Nasopharyngeal carcinoma (NPC) treatment by proposing a plan robustness evaluation method. Methods: 10 patients were selected for this study. A 2-arc volumetric-modulated arc therapy ( VMAT ) plan was gener- ated for each patient using Varian Eclipse (13.6 Version) treatment planning system ( TPS). 5 uncertainty plans (U-plans) were recalculated based on the first 5 times set-up errors acquired from cone-beam computer tomography (CBCT ). The dose differences of the original plan and perturbed plan corresponded to the plan robustness for the structure. Tumor control probability ( TCP) and normal tissues complication probability (NTCP) were calculated for biological evaluation. Results: The mean dose differences of D and D (ΔD and ΔD ) of PTVp were respectively 3.30 Gy and 98% 95% 98% 95% 2.02 Gy. The ΔD and ΔD of CTVp were 1.12 Gy and 0.58 Gy. The ΔD and ΔD of CTVn were 1.39 Gy and 98% 95% 98% 95% 1.03 Gy, distinctively lower than those in PTVn (2.8 Gy and 2.0 Gy). The CTV-to-PTV margin increased the robustness of CT Vs. The ΔD and ΔD of GTVp were 0.56 Gy and 0.33 Gy. GTVn exhibited strong robustness with little variation 98% 95% of D (0.64 Gy) and D (0.39 Gy). No marked mean dose variations of D were seen. The mean reduction of TCP 98% 95% mean (ΔTCP) in GTVp and CTVp were respectively 0.4% and 0.3%. The mean ΔTCPs of GTVn and CTVn were 0.92% and 1.3% respectively. The CTV exhibited the largest ΔTCP (2.2%). In OARs, the brain stem exhibited weak robustness due to their locations in the vicinity of PTV. Bilateral parotid glands were sensitive to set-up uncertainty with a mean reduc- tion of NTCP (ΔNTCP) of 6.17% (left) and 7.70% (right). The D of optical nerves and lens varied slightly. max Conclusion: VMAT plans had a strong sensitivity to set-up uncertainty in NPC radiotherapy, with increasing risk of underdose of tumor and overdose of vicinal OARs. We proposed an effective method to evaluate the plan robustness of VMAT plans. Plan robustness and complexity should be taken into account in photon radiotherapy. *Correspondence: dingzhen0909@163.com; xiangxiaoyong16@163.com Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 113 Baohe Rd, Longgang District, Shenzhen City 518116, Guangdong Province, People’s Republic of China © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecom- mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Ding et al. Radiation Oncology (2022) 17:1 Page 2 of 10 Keywords: Robustness, Tumor control probability, Normal tissue complication probability, Set-up uncertainty Introduction Methods Radiotherapy (RT) is the main strategy for Naso- Patient selection and delineation pharyngeal carcinoma (NPC) [1]. Owing to large irra- We retrospectively evaluated treatment plans for 10 NPC diation volumes, complex and intricate anatomical patients treated in our center. The clinical characteris - structures, precision dose coverage, and organ at risk tics of the patients enrolled in this study were shown in (OAR) sparing were crucial in NPC radiotherapy [2]. Table  1. All the patients were immobilized by a thermo- Volumetric arc radiotherapy (VMAT) had been widely plastic mask in a supine position. The CT image with a used in NPC radiotherapy, for VMAT performed opti- 2.5 mm slice thickness was acquired using a 16-slice CT mized dose distribution and OAR sparing by con- scanner (GE Discovery RT, GE Healthcare, Chicago, IL, tinuous variation of multi machine parameters [3]. USA). The target volumes and organs at risk (OARs) were However, increased plan complexity elevated risk of delineated by the same clinician. The gross tumor volume dose calculation and delivery, for more complex plans (GTV) consisted of GTV of the primary (GTVp) and required smaller and irregular beam apertures, larger GTV of lymph nodes (GTVn). The clinical target volume tongue-and groove effects, and greater extent modula- (CTV) consisted of CTVp and CTVn. The planned tar - tion of machine parameters, including gantry rotation get volume (PTV) included PTVp, PTVn, and PTV. All speed, dose rate, and multi leaf collimator (MLC) posi- the GTVs, CTVs, and PTVs were contoured by the same tion [4, 5]. VMAT plans may show the sensitivity of oncologist based on international guidelines [10]. dose delivery to subtle deviations, including machine parameters and target motion [4, 6]. Image guidance, such as the cone-beam computed Treatment plans and uncertainty plans tomography (CBCT) has been widely used in posi- A 2-arc volumetric-modulated arc therapy (VMAT) plan tion verification to reduce patient set-up uncertainty was generated for each patient using Varian Eclipse (13.6 [7]. The protocol of imaging frequency varies among Version,) treatment planning system (TPS) modeled for centers to balance the treatment efficiency and accu- the VitalBeam (Varian, Palo Alto, US) linac. Arc 1 (A1) racy. The unknown remaining fractions may result in rotate clockwise from 181° to 179°, and the arc 2 (A2) unexpected dose deviation and potential tumor recur- rotates counterclockwise from 179° to 181°. Collimator rence [8]. For this purpose, we aimed to study the sen- angles were set at ± 10°. The prescription doses of PTVp, sitivity of highly optimized VMAT plans to geometry PTVn, and PTV were 69.96 Gy, 68.31 Gy, and 59.40 Gy in deviation to make a more complete description of dose 33 fractions, respectively. delivery for complex plans. 5 set-up uncertainties were introduced on the origi- Treatment plan robustness is the degree of resiliency nal VMAT plan, shifting the isocenter from its refer- of the required dose distribution to these uncertain- ence position according to the set-up errors acquired by ties and varies with the treatment site, technique, and CBCT. The U-plans, representing the perturbed plans method. Yock’s [9] report reviewed robustness analysis introduced set-up uncertainties, were calculated for 33 methods and their dosimetric effects, to promote reli- able plan evaluation and dose reporting, particularly during clinical trials conducted across institutions and Table 1 Patients characteristics treatment modalities. The concept of robustness had Patient # Age Sex Stage been widely used in proton treatment plans for the sharp distal fall-off and scattering characteristics but 1 57 Male T1N1M0 was ignored in photon radiotherapy [5]. We adopted a 2 62 Male T4N2M0 plan robustness quantification method to address the 3 68 Male T3N2M0 sensitivity of VMAT plans to geometric uncertainty 4 27 Male T1N2M0 based on the daily CBCT shifts. Besides, the tumor 5 28 Female T1N1M0 control probability (TCP) and normal tissues com- 6 68 Male T1N1M0 plication probability (NTCP) models were applied to 7 67 Male T2N2M0 evaluate the potential biological dose differences. 8 43 Male T3N0M0 9 54 Male T1N1M0 10 38 Male T1N1M0 Ding  et al. Radiation Oncology (2022) 17:1 Page 3 of 10 Table 2 Evaluated items of PTVs and OARs from the maximum value and corresponded to the plan robustness for the structure. PTVs/OARs Evaluated items PTVp, PTVn, PTV ΔD , ΔD , 2cc 98% TCP and NTCP evaluation ΔD , ΔD 95% mean, Biological models have been proposed to predict radio- ΔTCP biological response to dose after irradiation [11, 12]. The CTVp, CTVn, CTV TCP and NTCP values were calculated to evaluate the GTVp, GTVn biological effects. We use the Schultheiss logit model pro - Brain Stem, Brain Stem PRV ΔD ΔNTCP max, posed by Niemierko [13]. We calculated the TCP accord- Spinal Cord, Spinal Cord PRV ing to Eq.  (1) with the parameters: T CD = 61.59  Gy, Lens L, Lens R γ = 3.38 [14]. Optic Nerve L, Optic Nerve R, Optic Chiasma Parotid L, Parotid R ΔD ΔNTCP mean, 1 TCP = 4γ PTV, planning target volume; PTVp, planning target volume of GTVp; PTVn, 50 (1) TCD 1 + planning target volume of GTVn; CTV, clinical target volume; CTVp, primary EUD tumor sites and their invasion range; CTVn, the clinical target volume of GTVn; GTVp, the clinical target volume of GTVp; GTVn, cervical metastatic lymph TCD is the dose of radiation that locally controls 50% node. D and D represented the mean dose and the maximum dose. D 50 mean max x% represented the dose (in Gy) received by x% of the volume, V the volume (in of tumors. The γ is the change in TCP expected because y Gy percentage) received by y Gy. D the dose (in Gy) received by a volume of 2 2cc of a 1% change in dose about the T CD . We calculated cm the NTCP [14] according to Eq. (2) x−TD ( ) EUD 2σ (2) NTCP = √ ∫ e dx σ 2π −∞ The σ was calculated by Eq. (3) σ = mTD 50 (3) The EUD, representing equivalent uniform dose, was calculated according to Eq. (4)   V D  i  i i EUD = �   (4) Fig. 1 Steps in robustness and biological evaluation of volumetric arc radiotherapy ( VMAT ) of NPC. U1 ~ U5 represented 5 set-up TD is the tolerance dose yielding a 50% complica- uncertainties acquired from the first 5 times daily CBCT. T-plan: tion rate in the normal organ. V is the volume at dose D . i i Treatment plan; U-plan: Uncertainty plan Parameter m and n are specific dose–response constants [15]. Statistical analysis fractions to facilitate the dose comparison. The evaluated There are 1  T-plan and 5 U-plans for each patient. The items of PTVs and OARs were listed in Table 2 (Fig. 1). dose differences were calculated by the absolute value of the minimum value subtracted from the maximum value and were explicit by mean value (minimum value to max- Robustness quantification method imum value). The dose deviations of D, D, D , and 95% 98% 2cc There are 1 treatment plan (T-plan) and 5 uncertainty D of CTVs, GTVs, and PTVs were chosen. D was mean max plans (U-plans) for each patient. The dose values in the chosen for serial OARs and D for the bilateral parotid mean treatment and perturbed plans were displayed in the gland. The TCP and NTCP reduction were calculated. dose-volume histogram (DVH) curves. D represented x% the dose (in Gy) received by x% of the volume. D the 2cc 3 Results dose (in Gy) received by a volume of 2 c m. D and max Targets dose coverage D represented the maximum and mean dose (in mean Figure  2 shows a schematic of transversal dose distribu- Gy). Absolute differences ΔD, which could be calculated tions in 1 treatment plan and 5 U-plans. The transver - by the absolute value of the minimum value subtracted sal dose coverage varies due to set-up uncertainty. To Ding et al. Radiation Oncology (2022) 17:1 Page 4 of 10 visualize the dose difference, a color wash schematic of 3.30  Gy and 2.02  Gy. Decreased ΔD (1.12  Gy) and 98% differences in dose distributions is shown in Fig.  3. The ΔD (0.58  Gy) were seen in CTVp. The ΔD and 95% 98% maximum dose discrepancies were observed in marginal ΔD in GTVp were 0.56 Gy and 0.33 Gy, indicating that 95% zones of PTVs. The dose changes of OARs were also the CTV-to-PTV margin promoted the robustness of greater in the vicinity of marginal zones and lesser distal GTV and CTV. Similarly, the PTVn had the largest differ - to these areas. ence of D (2.77 Gy) and D (2.00 Gy). The ΔD and 98% 95% 98% The average dose difference was shown in Table  3. No ΔD of CTVn were 1.39 Gy and1.03 Gy. Minor dose dif- 95% obvious differences were found in D The mean dose ferences were observed in GTVn for both D (0.64 Gy) 2cc. 98% differences of D and D of PTVp were respectively and D (0.59  Gy). No marked mean dose variations of 98% 95% 95% Fig. 2 A schematic of transversal dose distributions in 1 treatment plan and 5 U-plans. The green volume represents PTV, the brown volume represents PTVn, and the red volume represents PTVp. The transversal dose coverage varies due to set-up uncertainty Fig. 3 An example of color wash schematic of dose difference bewteen the T-plan and one of the U-plan. The green, brown, and red volumes represent PTV, PTVn, and PTVp respectively Table 3 Dose difference of PTVs, CTVs, and GTVs in 10 patients Targets ΔD (Gy) ΔD (Gy) ΔD (Gy) ΔD (Gy) 2cc 98% 95% mean PTVp 0.23 (0.07–0.34) 3.30 (0.76–4.38) 2.02 (0.53–3.23) 0.31 (0.11–0.70) PTVn 0.36 (0.05–0.86) 2.77 (0.60–6.05) 2.00 (0.72–4.56) 0.65 (0.10–1.52) PTV 0.18 (0.03–0.35) 1.95 (0.26–3.20) 1.34 (0.27–2.01) 0.35 (0.05–0.57) CTVp 0.20 (0.04–0.35) 1.12 (0.38–3.85) 0.58 (0.23–1.50) 0.16 (0.05–0.30) CTVn 0.40 (0.08–0.75) 1.39 (0.17–5.81) 1.03 (0.43–4.10) 0.56 (0.12–1.43) CTV 0.19 (0.03–0.34) 1.17 (0.12–2.44) 0.72 (0.11–1.51) 0.28 (0.06–0.46) GTVp 0.28 (0.12–0.37) 0.56 (0.06–2.88) 0.33 (0.07–0.67) 0.22 (0.03–0.49) GTVn 0.39 (00.16–0.74) 0.64 (0.30–1.91) 0.59 (0.16–1.59) 0.44 (0.08–0.84) The results were exhibited by Mean (Minimum–Maximum) Ding  et al. Radiation Oncology (2022) 17:1 Page 5 of 10 Table 4 Dose difference of D or D in OARs in 10 patients D were seen. Superior robustness in PTV and CTV max mean mean was seen. Items OARs Dose (Gy) Table  4 showed the dose differences of OARs. ΔD Brain Stem 4.34 (1.50–11.10) max The ΔD of the brain stem and PRV were 4.34  Gy max Brain Stem PRV 6.21 (2.40–10.19) (1.50  Gy-11.10  Gy) and 6.21  Gy (2.40  Gy-10.19  Gy). Spinal Cord 2.86 (1.00–7.10) The ΔD of the spinal cord and PRV were 2.86  Gy max Spinal Cord PRV 3.54 (1.70–7.40) (1.00  Gy-7.10  Gy) and 3.64  Gy (1.70  Gy-7.40  Gy). Nar- Lens L 0.89 (0.20–2.80) rowed width of DVH bands was observed in the bilateral Lens R 0.79 (0.20–1.40) lens. Optical nerves performed marked dose difference Optical Nerve L 8.00 (1.80–17.40) of mean dose, which were 8.00 Gy, 8.66 Gy, and 8.81 Gy Optical Nerve R 8.66 (1.40–20.20) for optical nerve L,R, and chiasma. The D of bilateral mean Optic Chiasma 8.81 (1.80–20.80) parotid glands exhibited obvious changes. ΔD Parotid L 4.48 (2.47–7.28) A sample of dose-volume histograms (DVHs) of mean Parotid R 4.05 (2.01–6.00) PTVs, CTVs, and GTVs was shown in Fig.  4. The solid line represented the DVH of the treatment plan, and The results were exhibited by Mean (Minimum–Maximum) the 5 dashed lines represented the DVH of U-plans. The envelope was defined as the area between all the DVH Fig. 4 A sample of dose-volume histograms (DVHs) of PTVs, CTVs, and GTVs, compared for 1 treatment plan and 5 U-plans. The DVH curve in the solid line represented the treatment plan. The DVH curves in the dashed line represented 5 U-plans. A PTVp; B PTVn; C PTV; D CTVp; E CTVn; F CTV; G GTVn; H GTVp Ding et al. Radiation Oncology (2022) 17:1 Page 6 of 10 curves. The gradually narrowed envelope was seen in Superior robustness was seen in PTV (Fig.  4C) and PTVp (Fig.  4A), CTVp (Fig.  4D), and GTVp (Fig.  4G). CTV (Fig. 4F). PTVn (Fig.  4B) exhibited high sensitivity to set-up As to OARs (Fig.  5), the brain stem (Fig.  5A) and uncertainty. Narrowed width of the envelope was its PRV (Fig.  5B) exhibited weak robustness due to seen in CTVn (Fig.  4E). Sufficient dose coverage and their locations in the vicinity of PTVs. The spinal cord decreased robustness were noticed in GTVn (Fig.  4H). (Fig. 5C) and its PRV (Fig. 5D) had stronger robustness. Fig. 5 A sample of dose-volume histograms (DVHs) of OARs was compared for 1 treatment plan and 5 U-plans. The DVH curve in the solid line represented the treatment plan. The DVH curves in the dashed line represented 5 U-plans. A Brain Stem; B Brain Stem PRV; C Spinal Cord; D Spinal Cord PRV; E Parotid L; F Parotid R; G Optical Nerve L; H Optical Nerve R; I Optical Nerve Chimsa; J Lens L; K Lens R Ding  et al. Radiation Oncology (2022) 17:1 Page 7 of 10 Bilateral parotid glands (Fig.  5E. F) were sensitive to Discussion set-up uncertainty for their being partially enclosed VMAT plans exhibited strong sensitivity to geomet- PTVs. The D of bilateral optical nerves (Fig.  5G–I) ric deviation PTVp and PTVn with large ΔD and max 98% and lens(Fig. 5J, K) varied slightly. ΔD . In photon radiotherapy, the CTV-to-PTV mar- 95% gin method was adopted based on the Van Herk margin formula [16] in the margin-based treatment planning, to TCP and NTCP evaluation ensure the dose coverage of CTV by blurring dose distri- The TCP reduction (ΔTCP) was the mean absolute bution induced by systematic setup errors. Although the value of the minimum value subtracted from the maxi- CTV-to-PTV margin increased robustness in CTVp and mum value. For GTVp and CTVp, the ΔTCP value CTVn, the ΔD of CTVp and CTVn reached 1.12  Gy 98% was less than 1% (Fig.  6), indicating strong robust- and 1.39  Gy. The ΔD of GTVp and GTVn reached 98% ness to set-up uncertainty. A greater ΔTCP value was 0.56  Gy and 0.64  Gy. Similarly, considerable dose devia- observed in GTVn and CTVn. CTV had the largest tions were observed in D of CTVp, CTVn, PTVp, and 95% TCP reduction. PTVn. Although the margin method effectively improved We performed NTCP modeling analysis to evaluate the plan’s robustness by reducing sensitivity to the uncer- the dose variation of OARs (Fig.  7). The NTCP reduc - tainties, high risk remains. The dose variation of D and 95% tion (ΔNTCP) was obtained as the mean absolute value D in PTVs could reach a maximum of 6 Gy. The maxi - 98% of the minimum value subtracted from the maximum mum difference of D and D in CTVs and GTVs 95% 98% value. The average ΔNTCP of bilateral parotids reached could reach a maximum of 2.81  Gy. The maximum dif - 6.17% (left) and 7.70% (right) (Fig.  7). No significant ference of D of PTVs could reach 1.5  Gy. The study mean biological dose changes were found in OARs. of Dupic [17] indicated that the GTV D is a strong 98% reproducible significant predictive factor of local control for the brain. A sufficient dose of GTVs should be rigidly reached. Zhao et al. [18] performed a retrospective study of a total of 1,092 patients with NSCLC of clinical-stage T1-T2 N0M0 who were treated with SABR. They rec - ommended that both PTV D and PTV should be 95% mean considered for plan optimization other than gross tumor volume. When the physical dose changed, the biologi- cal effect followed. The ΔTCP in GTVp and CTVp were respectively 0.4% and 0.3%. However, ΔTCP of GTVn and CTVn were 0.92% and 1.3% respectively. The CTV had the largest mean variation of ΔTCP (2.2%). Under dosage in the targets may result in the likelihood of Fig. 6 Box plot showed the ΔTCP of all targets due to set-up tumor recurrence [19], for TCP predominately correlates uncertainties. The ΔTCP was the mean reduction of TCP Fig. 7 Box plot showed the ΔNTCP of OARs due to set-up uncertainties. The ΔNTCP was the mean reduction of NTCP Ding et al. Radiation Oncology (2022) 17:1 Page 8 of 10 with the minimum dose of tumor [13]. Plan robustness of Plan robustness qualification was always considered in photon radiotherapy should be taken into consideration. proton therapy to address sensitivity to uncertainties in Weak robustnesses and large dose variations were treatment planning [29]. In photon RT, the CTV-to-PTV observed in the OARs in the vicinity locations of PTVs. margin method had been adopted to assure dose cov- In this study, the average ΔD of the brain stem and spi- erage with uniform margin, instead of plan robustness max nal cord reached 1.85 Gy and 1.51 Gy. Previous research qualification. However, the CTV-to-PTV margin method reported that brain stem necrosis, MIR-based evidence has limitations, such as relying on the so-called static of injury, or neurologic toxicities were related to pho- dose cloud approximation. A phantom study conducted ton radiotherapy [20–22]. Using conventional fractiona- by Englesman et al. [30] observed a maximum decreased tion of 1.8–2  Gy/fraction to the full-thickness cord, the dose of 5% with respiratory motion uncertainty. Guer- estimated risk of myelopathy is < 1% and < 10% at 54  Gy reiro [31] evaluated the robustness against inter-fraction and 61  Gy, respectively [23]. For bilateral optic nerves anatomical changes between photon and proton dose and chiasm, the average ΔD were 4.59  Gy, 5.00  Gy distributions and found that daily anatomical changes max and 5.01 Gy. There is a shred of strong evidence that evi - proved to affect the target coverage of VMAT dose dis - dence radiation tolerance is increased with a reduction tributions to a higher extent. Our results indicated that in the dose per fraction [14, 24]. In radiotherapy of NPC, CTV-to-PTV margin increased robustness of CTV and the bilateral parotids are often under irradiation. Sali- GTV, reduced but did not remove the risk of underdos- vary dysfunction has been correlated to the mean parotid age. This plan robustness quantification method could be gland dose, with recovery occurring with time [25–27]. adopted in highly optimized clinical treatment plans to The average ΔNTCP of bilateral parotids reached 6.17% make a more complete dose description. (left) and 7.70% (right), which sharply increased the risk Besides, the robustness optimization methods had of parotid gland dysfunction. The actual irradiation dose been developed by incorporating uncertainty in plan of vicinal OAR may be biased upwards due to the set-up optimization, for CTV should receive the prescribed dose uncertainty. depending on desired dose distribution and dose fall-off Based on the results in this study, it is not hard to near the target rather than geometric margin [32]. Lowe notice the strong sensitivity of highly optimized VMAT et al. [33] believed robustness optimization was an effec - plans to geometric deviations. This generates worries tive method to reduce dose to normal tissues that would about the accuracy of treatment dose delivery. ‘Plan be unnecessarily irradiated with the CTV-to-PTV mar- quality assessment’ had been proposed firstly by the 3rd gin concept. Dosimetric consequences of uncertainty, Physics ESTRO Workshop in 2019. Plan quality could such as equivalent uniform dose (EUD), TCP, and NTCP be understood as the clinical suitability of the delivered were also recommended. dose distribution that can be realistically expected from Among the limitation of the study, it is important to a treatment plan [4]. Plan quality depends on the plan highlight that the first 5 times set-up errors acquired robustness and complexity of the treatment plan. from CBCT did not represent the actual set-up uncer- Intricate anatomical structures, precise dose coverage, tainty, for the set-up error consisted of systematic and and optimal OARs sparing generated highly optimized random errors. Additionally, the patient anatomy change VMAT plans in NPC radiotherapy. High-degree modu- and rotation have not been taken into account. As a pos- lated radiotherapy techniques increased plan complexity, sible solution, adaptive radiotherapy (ART) could help to with modulation of machine parameters, such as gantry solve this problem [34]. We aimed to simulate the scenar- rotate speed, continuously varied dose rate, and position ios introduced to set up uncertainties, and visualize the of MLC. A study by Hirashima [28] uses plan complex- necessity of robustness quantification is highly optimized ity and dosiomics features to predict the performance for photon RT. Treatment plan robustness analysis provides gamma passing rate, indicating the correlation between a more complete description of the dose delivered in the plan complexity and the accuracy of treatment plan dose presence of uncertainties, and may lead to future dosi- delivery. Many commercial TPSs now offer the possibil - metric studies with improved accuracy. ity to control plan complexity, such as controlling the minimum size and monitor unit (MU) (Phillips Pinnacle, Conclusions Amsterdam, the Netherlands), aperture shape controller VMAT plans had a strong sensitivity to set-up uncer- (ASC) (Varian Eclipse, Palo Alto, CA, USA), and modu- tainty in NPC radiotherapy, due to the high degree of lation factor (MF) (TomoTherapy, Accuray Incorporated, modulation. We proposed an effective method to evalu - Sunnyvale, CA, USA). The balance should be reached ate the plan robustness of VMAT plans. Plan robustness between dosimetric improvement and dose delivery and complexity should be taken into account in photon accuracy. radiotherapy techniques with high degree optimization. Ding  et al. Radiation Oncology (2022) 17:1 Page 9 of 10 5. Korevaar EW, Habraken SJM, Scandurra D, et al. 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Journal

Radiation OncologySpringer Journals

Published: Jan 3, 2022

Keywords: Robustness; Tumor control probability; Normal tissue complication probability; Set-up uncertainty

References