VMAT plans exhibited strong sensitivity to geometric deviation PTVp and PTVn with large ΔD98% and ΔD95%. In photon radiotherapy, the CTV-to-PTV margin method was adopted based on the Van Herk margin formula [16] in the margin-based treatment planning, to ensure the dose coverage of CTV by blurring dose distribution induced by systematic setup errors. Although the CTV-to-PTV margin increased robustness in CTVp and CTVn, the ΔD98% of CTVp and CTVn reached 1.12 Gy and 1.39 Gy. The ΔD98% of GTVp and GTVn reached 0.56 Gy and 0.64 Gy. Similarly, considerable dose deviations were observed in D95% of CTVp, CTVn, PTVp, and PTVn. Although the margin method effectively improved the plan’s robustness by reducing sensitivity to the uncertainties, high risk remains. The dose variation of D95% and D98% in PTVs could reach a maximum of 6 Gy. The maximum difference of D95% and D98% in CTVs and GTVs could reach a maximum of 2.81 Gy. The maximum difference of Dmean of PTVs could reach 1.5 Gy. The study of Dupic [17] indicated that the GTV D98% is a strong 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 recommended that both PTV D95% and PTVmean should be considered for plan optimization other than gross tumor volume. When the physical dose changed, the biological 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 tumor recurrence [19], for TCP predominately correlates with the minimum dose of tumor [13]. Plan robustness of photon radiotherapy should be taken into consideration.

Weak robustnesses and large dose variations were observed in the OARs in the vicinity locations of PTVs. In this study, the average ΔDmax of the brain stem and spinal cord reached 1.85 Gy and 1.51 Gy. Previous research reported that brain stem necrosis, MIR-based evidence of injury, or neurologic toxicities were related to photon radiotherapy [20,21,22]. Using conventional fractionation of 1.8–2 Gy/fraction to the full-thickness cord, the estimated risk of myelopathy is < 1% and < 10% at 54 Gy and 61 Gy, respectively [23]. For bilateral optic nerves and chiasm, the average ΔDmax were 4.59 Gy, 5.00 Gy and 5.01 Gy. There is a shred of strong evidence that evidence radiation tolerance is increased with a reduction in the dose per fraction [14, 24]. In radiotherapy of NPC, the bilateral parotids are often under irradiation. Salivary dysfunction has been correlated to the mean parotid gland dose, with recovery occurring with time [25,26,27]. The average ΔNTCP of bilateral parotids reached 6.17% (left) and 7.70% (right), which sharply increased the risk of parotid gland dysfunction. The actual irradiation dose of vicinal OAR may be biased upwards due to the set-up uncertainty.

Based on the results in this study, it is not hard to notice the strong sensitivity of highly optimized VMAT plans to geometric deviations. This generates worries about the accuracy of treatment dose delivery. ‘Plan quality assessment’ had been proposed firstly by the 3rd Physics ESTRO Workshop in 2019. Plan quality could be understood as the clinical suitability of the delivered dose distribution that can be realistically expected from a treatment plan [4]. Plan quality depends on the plan robustness and complexity of the treatment plan.

Intricate anatomical structures, precise dose coverage, and optimal OARs sparing generated highly optimized VMAT plans in NPC radiotherapy. High-degree modulated radiotherapy techniques increased plan complexity, with modulation of machine parameters, such as gantry rotate speed, continuously varied dose rate, and position of MLC. A study by Hirashima [28] uses plan complexity and dosiomics features to predict the performance for gamma passing rate, indicating the correlation between plan complexity and the accuracy of treatment plan dose delivery. Many commercial TPSs now offer the possibility to control plan complexity, such as controlling the minimum size and monitor unit (MU) (Phillips Pinnacle, Amsterdam, the Netherlands), aperture shape controller (ASC) (Varian Eclipse, Palo Alto, CA, USA), and modulation factor (MF) (TomoTherapy, Accuray Incorporated, Sunnyvale, CA, USA). The balance should be reached between dosimetric improvement and dose delivery accuracy.

Plan robustness qualification was always considered in proton therapy to address sensitivity to uncertainties in treatment planning [29]. In photon RT, the CTV-to-PTV margin method had been adopted to assure dose coverage with uniform margin, instead of plan robustness qualification. However, the CTV-to-PTV margin method has limitations, such as relying on the so-called static dose cloud approximation. A phantom study conducted by Englesman et al. [30] observed a maximum decreased dose of 5% with respiratory motion uncertainty. Guerreiro [31] evaluated the robustness against inter-fraction anatomical changes between photon and proton dose distributions and found that daily anatomical changes proved to affect the target coverage of VMAT dose distributions to a higher extent. Our results indicated that CTV-to-PTV margin increased robustness of CTV and GTV, reduced but did not remove the risk of underdosage. This plan robustness quantification method could be adopted in highly optimized clinical treatment plans to make a more complete dose description.

Besides, the robustness optimization methods had been developed by incorporating uncertainty in plan optimization, for CTV should receive the prescribed dose depending on desired dose distribution and dose fall-off near the target rather than geometric margin [32]. Lowe et al. [33] believed robustness optimization was an effective method to reduce dose to normal tissues that would be unnecessarily irradiated with the CTV-to-PTV margin concept. Dosimetric consequences of uncertainty, such as equivalent uniform dose (EUD), TCP, and NTCP were also recommended.

Among the limitation of the study, it is important to highlight that the first 5 times set-up errors acquired from CBCT did not represent the actual set-up uncertainty, for the set-up error consisted of systematic and random errors. Additionally, the patient anatomy change and rotation have not been taken into account. As a possible solution, adaptive radiotherapy (ART) could help to solve this problem [34]. We aimed to simulate the scenarios introduced to set up uncertainties, and visualize the necessity of robustness quantification is highly optimized photon RT. Treatment plan robustness analysis provides a more complete description of the dose delivered in the presence of uncertainties, and may lead to future dosimetric studies with improved accuracy.

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